Updated on 2023/09/29

写真a

 
OGI Tomoo
 
Organization
Research Institute of Environmental Medicine Division of Stress Adaptation and Protection Professor
Graduate School
Graduate School of Medicine
Title
Professor

Degree 1

  1. 博士(理学) ( 2001.3   京都大学 ) 

Research Interests 14

  1. DNA repair; human genetics; nucleotide excision repair; genome

  2. 転写と共役したヌクレオチド除去修復

  3. 突然変異

  4. 発がん

  5. 放射線DNA損傷

  6. Human Genetics

  7. 乳癌

  8. ヌクレオチド除去修復

  9. タンパク質間相互作用

  10. ゲノム医科学

  11. DNA損傷修復

  12. DNA repair; human genetics; nucleotide excision repair; genome

  13. DNA修復

  14. BRCA2

Research Areas 6

  1. Life Science / Dermatology

  2. Life Science / Pathological biochemistry

  3. Environmental Science/Agriculture Science / Radiation influence

  4. Life Science / Medical biochemistry

  5. Environmental Science/Agriculture Science / Chemical substance influence on environment

  6. Life Science / Molecular biology

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Research History 3

  1. Nagoya University

    2021.1

  2. Nagoya University   Research Institute of Environmental Medicine (RIeM)   Professor

    2015.4

  3. Nagoya University   Research Institute of Environmental Medicine Division of Stress Adaptation and Protection   Professor

    2015.4

 

Papers 136

  1. Next-generation sequencing-based detection of Ureaplasma in the gastric fluid of neonates with respiratory distress and chorioamnionitis

    Okumura Toshihiko, Horiba Kazuhiro, Tetsuka Nobuyuki, Sato Yoshiaki, Sugiyama Yuichiro, Haruta Kazunori, Yamaguchi Makoto, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Ogi Tomoo, Hayakawa Masahiro, Ito Yoshinori

    JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE   Vol. 36 ( 1 ) page: 2207113   2023.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Maternal-Fetal and Neonatal Medicine  

    Background: Respiratory distress is common in neonates admitted to neonatal intensive care units. Additionally, infectious diseases such as intrauterine infections or vertical transmission are important underlying causes of respiratory failure. However, pathogens often cannot be identified in neonates, and there are many cases in which antibacterial drugs are empirically administered. Next-generation sequencing (NGS) is advantageous in that it can detect trace amounts of bacteria that cannot be detected by culturing or bacteria that are difficult to cultivate. However, there are few reports on the diagnosis of infectious diseases using NGS in the neonatal field, especially those targeting respiratory distress. Objective: The purpose of our study was to investigate the microorganisms associated with neonatal respiratory distress and to determine whether less invasive collection specimens such as plasma and gastric fluid are useful. Methods: Neonates were prospectively recruited between January and August 2020 from Nagoya University Hospital. The inclusion criteria were as follows: 1) admission to the neonatal intensive care unit; 2) respiratory distress presentation within 48 h of birth; and 3) suspected infection, collection of blood culture, and administration of antibiotics. Plasma samples and blood cultures were simultaneously collected. Gastric fluid samples were also collected if the patient was not started on enteral nutrition. Information on the patients and their mothers were collected from the medical records. DNA was extracted from 140 µL of plasma and gastric fluid samples. DNA sequencing libraries were prepared, and their quality was analyzed. DNA libraries were sequenced using high-throughput NGS. The NGS data of plasma and gastric fluid samples were analyzed using the metagenomic pipeline PATHDET, which calculated the number of reads assigned to microorganisms and their relative abundance. Putative pathogens were listed. Results: Overall, 30 plasma samples and 25 gastric fluid samples from 30 neonates were analyzed. Microorganism-derived reads of gastric fluid samples were significantly higher than those of plasma samples. Transient tachypnea of the newborn was the most common cause of respiratory distress with 13 cases (43%), followed by respiratory distress syndrome with 7 cases (23%). There were 8 cases (29%) of chorioamnionitis and 7 cases (25%) of funisitis pathologically diagnosed. All blood cultures were negative, and only two gastric fluid cultures were positive for group B Streptococcus (Patient 15) and Candida albicans (Patient 24). Putative pathogens that met the positive criteria for PATHET were detected in four gastric fluid samples, one of which was group B Streptococcus from Patient 15. In the gastric fluid sample of Patient 24, Candida albicans were detected by NGS but did not meet the positive criteria for PATHDET. Cluster analysis of the plasma samples divided them into two study groups, and the indicator genera of each cluster (Phormidium or Toxoplasma) are shown in Figure 1. Clinical findings did not show any significant differences between the two groups. Cluster analysis of the gastric fluid samples divided them into three study groups, and the indicator genera of each cluster (Ureaplasma, Nostoc, and Streptococcus) are shown in Figure 2. The incidence rate of chorioamnionitis was significantly higher in Ureaplasma group than in the other two groups. Conclusion: Gastric fluid may be useful for assessing neonatal patients with respiratory distress. To the best of our knowledge, this was the first study to reveal that the presence of Ureaplasma in the gastric fluid of neonates with respiratory distress was associated with chorioamnionitis. The early diagnosis of intra-amniotic infections using gastric fluid and its treatment may change the treatment strategy for neonatal respiratory distress. Screening for Ureaplasma in neonates with respiratory distress may reduce the need for empirical antibiotic administration. Further research is required to confirm these findings.

    DOI: 10.1080/14767058.2023.2207113

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  2. Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH. International journal

    Michiko Itoh, Atsushi Tamura, Sayaka Kanai, Miyako Tanaka, Yohei Kanamori, Ibuki Shirakawa, Ayaka Ito, Yasuyoshi Oka, Isao Hidaka, Taro Takami, Yasushi Honda, Mitsuyo Maeda, Yasuyuki Saito, Yoji Murata, Takashi Matozaki, Atsushi Nakajima, Yosky Kataoka, Tomoo Ogi, Yoshihiro Ogawa, Takayoshi Suganami

    The Journal of experimental medicine   Vol. 220 ( 11 )   2023.11

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    Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

    DOI: 10.1084/jem.20220681

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  3. Extremely low-frequency electromagnetic field induces acetylation of heat shock proteins and enhances protein folding.

    Huang Z, Ito M, Zhang S, Toda T, Takeda JI, Ogi T, Ohno K

    Ecotoxicology and environmental safety   Vol. 264   page: 115482   2023.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Ecotoxicology and Environmental Safety  

    The pervasive weak electromagnetic fields (EMF) inundate the industrialized society, but the biological effects of EMF as weak as 10 µT have been scarcely analyzed. Heat shock proteins (HSPs) are molecular chaperones that mediate a sequential stress response. HSP70 and HSP90 provide cells under undesirable situations with either assisting covalent folding of proteins or degrading improperly folded proteins in an ATP-dependent manner. Here we examined the effect of extremely low-frequency (ELF)-EMF on AML12 and HEK293 cells. Although the protein expression levels of HSP70 and HSP90 were reduced after an exposure to ELF-EMF for 3 h, acetylations of HSP70 and HSP90 were increased, which was followed by an enhanced binding affinities of HSP70 and HSP90 for HSP70/HSP90-organizing protein (HOP/STIP1). After 3 h exposure to ELF-EMF, the amount of mitochondria was reduced but the ATP level and the maximal mitochondrial oxygen consumption were increased, which was followed by the reduced protein aggregates and the increased cell viability. Thus, ELF-EMF exposure for 3 h activated acetylation of HSPs to enhance protein folding, which was returned to the basal level at 12 h. The proteostatic effects of ELF-EMF will be able to be applied to treat pathological states in humans.

    DOI: 10.1016/j.ecoenv.2023.115482

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  4. Live cell transcription-coupled nucleotide excision repair dynamics revisited.

    Llerena Schiffmacher DA, Kliza KW, Theil AF, Kremers GJ, Demmers JAA, Ogi T, Vermeulen M, Vermeulen W, Pines A

    DNA repair   Vol. 130   page: 103566   2023.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:DNA Repair  

    Transcription–blocking lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which prevents DNA damage-induced cellular toxicity and maintains proper transcriptional processes. TC-NER is initiated by the stalling of RNA polymerase II (RNAPII), which triggers the assembly of TC-NER-specific proteins, namely CSB, CSA and UVSSA, which collectively control and drive TC-NER progression. Previous research has revealed molecular functions for these proteins, however, exact mechanisms governing the initiation and regulation of TC-NER, particularly at low UV doses have remained elusive, partly due to technical constraints. In this study, we employ knock-in cell lines designed to target the endogenous CSB gene locus with mClover, a GFP variant. Through live cell imaging, we uncover the intricate molecular dynamics of CSB in response to physiologically relevant UV doses. We showed that the DNA damage-induced association of CSB with chromatin is tightly regulated by the CSA-containing ubiquitin-ligase CRL complex (CRL4CSA). Combining the CSB-mClover knock-in cell line with SILAC-based GFP-mediated complex isolation and mass-spectrometry-based proteomics, revealed novel putative CSB interactors as well as discernible variations in complex composition during distinct stages of TC-NER progression. Our work not only provides molecular insight into TC-NER, but also illustrates the versatility of endogenously tagging fluorescent and affinity tags.

    DOI: 10.1016/j.dnarep.2023.103566

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  5. Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes.

    Takeichi T, Hamada T, Yamamoto M, Ito Y, Kawaguchi A, Kobashi H, Yoshikawa T, Koga H, Ishii N, Nakama T, Muro Y, Ogi T, Akiyama M

    The Journal of dermatology     2023.9

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    DOI: 10.1111/1346-8138.16967

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  6. Inducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells. International journal

    Akiko Tomita, Hiroyuki Sasanuma, Tomoo Owa, Yuka Nakazawa, Mayuko Shimada, Takahiro Fukuoka, Tomoo Ogi, Shinichiro Nakada

    Nature communications   Vol. 14 ( 1 ) page: 5607 - 5607   2023.9

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    CRISPR/Cas9-mediated gene editing has great potential utility for treating genetic diseases. However, its therapeutic applications are limited by unintended genomic alterations arising from DNA double-strand breaks and random integration of exogenous DNA. In this study, we propose NICER, a method for correcting heterozygous mutations that employs multiple nicks (MNs) induced by Cas9 nickase and a homologous chromosome as an endogenous repair template. Although a single nick near the mutation site rarely leads to successful gene correction, additional nicks on homologous chromosomes strongly enhance gene correction efficiency via interhomolog homologous recombination (IH-HR). This process partially depends on BRCA1 and BRCA2, suggesting the existence of several distinct pathways for MN-induced IH-HR. According to a genomic analysis, NICER rarely induces unintended genomic alterations. Furthermore, NICER restores the expression of disease-causing genes in cells derived from genetic diseases with compound heterozygous mutations. Overall, NICER provides a precise strategy for gene correction.

    DOI: 10.1038/s41467-023-41048-5

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  7. Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum. International journal

    Chikako Senju, Yuka Nakazawa, Taichi Oso, Mayuko Shimada, Kana Kato, Michiko Matsuse, Mariko Tsujimoto, Taro Masaki, Yasushi Miyazaki, Satoshi Fukushima, Satoshi Tateishi, Atsushi Utani, Hiroyuki Murota, Katsumi Tanaka, Norisato Mitsutake, Shinichi Moriwaki, Chikako Nishigori, Tomoo Ogi

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 120 ( 27 ) page: e2217423120   2023.7

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    Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

    DOI: 10.1073/pnas.2217423120

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  8. Utility of nanopore sequencing for detecting pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure

    Yamaguchi Makoto, Horiba Kazuhiro, Haruta Kazunori, Takeuchi Suguru, Suzuki Takako, Torii Yuka, Kawabe Shinji, Wada Sho, Ikeyama Takanari, Ito Yoshinori, Ogi Tomoo, Kawada Jun-ichi

    JOURNAL OF CLINICAL VIROLOGY PLUS   Vol. 3 ( 2 )   2023.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Clinical Virology Plus  

    RNA viruses are the most frequent pathogens responsible for respiratory infections, particularly in pediatric patients. Next-generation sequencing, represented by Illumina sequencing, is one of the most comprehensive methods for identifying pathogens. Nanopore sequencing has been used to identify and analyze pathogens with a shorter sequencing time. In this study, we evaluated the utility of nanopore sequencing for the detection of RNA viruses in bronchoalveolar lavage fluid (BALF) of pediatric patients with respiratory failure. Using the seven BALF samples, we first compared the nanopore and Illumina sequencing results. The nanopore sequencing detected the same RNA viruses as the Illumina sequencing. Subsequently, BALF samples from 24 additional pediatric patients with respiratory failure were analyzed by nanopore sequencing, and RNA viral pathogens were detected in 10 out of 24 patients. Among these 10 patients, nanopore sequencing identified the same viral pathogens as detected by the PCR and viral antigen tests in five patients. Furthermore, additional RNA viral pathogens were detected by nanopore sequencing with high genome coverage in five patients that were not detected by PCR and viral antigen tests. In conclusion, nanopore sequencing could comprehensively detect RNA viral pathogens in BALF samples with equivalent sensitivity and genome coverage as Illumina sequencing. This rapid sequencing platform may be more beneficial for detecting RNA viruses in clinical settings.

    DOI: 10.1016/j.jcvp.2023.100154

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  9. A case of Cockayne syndrome with unusually mild clinical manifestations

    Tsujimoto Mariko, Nakano Eiji, Nakazawa Yuka, Kanda Fumio, Ueda Takehiro, Ogi Tomoo, Nishigori Chikako

    JOURNAL OF DERMATOLOGY   Vol. 50 ( 4 ) page: 541 - 545   2023.4

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    We present a mild case of Cockayne syndrome that was referred to us with an extreme sunburn at the age of 3. In early teens, although her cutaneous symptoms alleviated without any medications, she developed tremor and dysarthria. Neurological examination and brain imaging suggested demyelination disorders. The patient's cells indicated a reduced recovery of RNA synthesis, which was partially restored by the introduction of CSB (Cockayne Syndrome B)-cDNA. In addition, her cells indicated a substantially reduced level of CSB protein. Despite the insidious progression of neurological symptoms, she gave birth to a child. Such mild cases of Cockayne syndrome may be misdiagnosed.

    DOI: 10.1111/1346-8138.16679

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  10. Outcomes of embolization procedures for type II endoleaks following endovascular abdominal aortic repair

    Iwakoshi S., Ogawa Y., Dake M.D., Ono Y., Higashihara H., Ikoma A., Nakai M., Taniguchi T., Ogi T., Kawada H., Tamura A., Ieko Y., Tanaka R., Sohgawa E., Nagatomi S., Woodhams R., Ikeda O., Mori K., Nishimaki H., Koizumi J., Senokuchi T., Hagihara M., Shimohira M., Takasugi S., Imaizumi A., Higashiura W., Sakaguchi S., Ichihashi S., Inoue T., Inoue T., Kichikawa K.

    Journal of Vascular Surgery   Vol. 77 ( 1 ) page: 114 - 121.e2   2023.1

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    Objective: The objective of this study was to investigate the mid-term outcomes of embolization procedures for type II endoleak after endovascular abdominal aortic repair, and clarify the risk factors for aneurysm enlargement after embolization procedures. Methods: This was a retrospective multicenter registry study enrolling patients who underwent embolization procedures for type II endoleaks after EVAR from January 2012 to December 2018 at 19 Japanese centers. The primary end point was the rate of freedom from aneurysm enlargement, more than 5 mm in the aortic maximum diameter, after an embolization procedure. Demographic, procedural, follow-up, and laboratory data were collected. Continuous variables were summarized descriptively, and Kaplan-Meier analyses and a Cox regression model were used for statistical analyses. Results: A total of 315 patients (248 men and 67 women) were enrolled. The average duration from the initial embolization procedure to the last follow-up was 31.6 ± 24.6 months. The rates of freedom from aneurysm enlargement at 3 and 5 years were 55.4 ± 3.8% and 37.0 ± 5.2%, respectively. A multivariate analysis revealed that a larger aortic diameter at the initial embolization procedure and the presence of a Moyamoya endoleak, defined as heterogeneous contrast opacity with an indistinct faint border, were associated with aneurysm enlargement after embolization management. Conclusions: The embolization procedures were generally ineffective in preventing further expansion of abdominal aortic aneurysms in patients with type II endoleaks after EVAR, especially in patients with a large abdominal aortic aneurysm and/or a presence of a Moyamoya endoleak.

    DOI: 10.1016/j.jvs.2022.07.168

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  11. Two children with hypophosphatasia with a heterozygous c.1559delT variant in the ALPL gene, the most common variant in Japanese populations

    Kitoh Hiroshi, Izawa Masako, Kaneko Hiroshi, Kitamura Akiko, Matsuyama Saori, Kato Kohji, Ogi Tomoo

    BONE REPORTS   Vol. 17   page: 101626   2022.12

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    Hypophosphatasia (HPP), a genetic disorder characterized by decreased tissue-nonspecific alkaline phosphatase (TNSALP) activity, is caused by loss-of-function mutations in the ALPL gene, which encodes TNSALP. The most frequent pathogenic variant in Japanese patients with HPP is a frameshift mutation in the ALPL gene, c.1559delT, and its carrier frequency is reported to be one in 480 in the Japanese population. We report the cases of two Japanese children with HPP who had a heterozygous c.1559delT variant in the ALPL gene. One case (involving a neonate) exhibited respiratory insufficiency associated with vitamin B6 dependent convulsions, significant defective mineralization similar to the severe form of HPP, and extremely low ALP activity. Enzyme replacement therapy (ERT) using asfotase alfa promptly improved her respiratory insufficiency, bone mineralization, and maintained her motor development during infancy. The second case involved a 10-year-old boy who demonstrated diffuse musculoskeletal pain and weakness that progressively disturbed mobility. Although he showed no bony lesions, the clinical symptoms and biochemical abnormalities were compatible with childhood HPP. ERT successfully relieved the severe generalized pain and significantly improved motor function.

    DOI: 10.1016/j.bonr.2022.101626

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  12. A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review

    Tano Sho, Kotani Tomomi, Yoshihara Masato, Nakamura Noriyuki, Matsuo Seiko, Ushida Takafumi, Imai Kenji, Ito Miharu, Oka Yasuyoshi, Sato Emi, Hayashi Shin, Ogi Tomoo, Kajiyama Hiroaki

    MOLECULAR GENETICS AND METABOLISM REPORTS   Vol. 33   page: 100925   2022.12

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    Non-immune hydrops fetalis (NIHF) indicates the risk for stillbirth. Although the causes vary and most NIHFs have no identifiable cause, recent advances in exome sequencing have increased diagnostic rates. We report a case of NIHF that developed into a giant cystic hygroma complicated by maternal mirror syndrome. Trio-based exome sequencing showed a de novo heterozygous missense variant in the RIT1 (NM_006912: c.246 T > G [p.F82L]). The RIT1 variants are known causative variants of Noonan syndrome (NS; OMIM #163950). The location of the RIT1 variants in the previously reported NS cases with NIHF or/and maternal mirror syndrome was mainly in the switch II region, including the present case. While a further accumulation of cases is needed, exome sequencing, which can identify the variant type in detail, might help predict the phenotype and severity of NIHF.

    DOI: 10.1016/j.ymgmr.2022.100925

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  13. Ceramide analysis in combination with genetic testing may provide a precise diagnosis for self-healing collodion babies. Reviewed International journal

    Takuya Takeichi, Yusuke Ohno, Kana Tanahashi, Yasutoshi Ito, Ken Shiraishi, Ryo Utsunomiya, Satoshi Yoshida, Kenta Ikeda, Hayato Nomura, Shin Morizane, Koji Sayama, Tomoo Ogi, Yoshinao Muro, Akio Kihara, Masashi Akiyama

    Journal of lipid research   Vol. 63 ( 12 ) page: 100308 - 100308   2022.12

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    Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79*))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs*3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain fatty acid (FA) ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79*) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with non-invasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

    DOI: 10.1016/j.jlr.2022.100308

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  14. 経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

    有沢 友希, 武市 拓也, 伊藤 靖敏, 棚橋 華奈, 室 慶直, 荻 朋男, 秋山 真志

    加齢皮膚医学セミナー   Vol. 17 ( 2 ) page: 65 - 66   2022.12

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  15. Global landscape of replicative DNA polymerase usage in the human genome. International journal

    Eri Koyanagi, Yoko Kakimoto, Tamiko Minamisawa, Fumiya Yoshifuji, Toyoaki Natsume, Atsushi Higashitani, Tomoo Ogi, Antony M Carr, Masato T Kanemaki, Yasukazu Daigaku

    Nature communications   Vol. 13 ( 1 ) page: 7221 - 7221   2022.11

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    The division of labour among DNA polymerase underlies the accuracy and efficiency of replication. However, the roles of replicative polymerases have not been directly established in human cells. We developed polymerase usage sequencing (Pu-seq) in HCT116 cells and mapped Polε and Polα usage genome wide. The polymerase usage profiles show Polε synthesises the leading strand and Polα contributes mainly to lagging strand synthesis. Combining the Polε and Polα profiles, we accurately predict the genome-wide pattern of fork directionality plus zones of replication initiation and termination. We confirm that transcriptional activity contributes to the pattern of initiation and termination and, by separately analysing the effect of transcription on co-directional and converging forks, demonstrate that coupled DNA synthesis of leading and lagging strands is compromised by transcription in both co-directional and convergent forks. Polymerase uncoupling is particularly evident in the vicinity of large genes, including the two most unstable common fragile sites, FRA3B and FRA3D, thus linking transcription-induced polymerase uncoupling to chromosomal instability. Together, our result demonstrated that Pu-seq in human cells provides a powerful and straightforward methodology to explore DNA polymerase usage and replication fork dynamics.

    DOI: 10.1038/s41467-022-34929-8

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  16. Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test. International journal

    Chikako Senju, Yuka Nakazawa, Mayuko Shimada, Dai Iwata, Michiko Matsuse, Katsumi Tanaka, Yasushi Miyazaki, Shinichi Moriwaki, Norisato Mitsutake, Tomoo Ogi

    Frontiers in pediatrics   Vol. 10   page: 1048002 - 1048002   2022.11

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    Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

    DOI: 10.3389/fped.2022.1048002

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  17. Performance of Nanopore and Illumina Metagenomic Sequencing for Pathogen Detection and Transcriptome Analysis in Infantile Central Nervous System Infections

    Horiba Kazuhiro, Torii Yuka, Aizawa Yuta, Yamaguchi Makoto, Haruta Kazunori, Okumura Toshihiko, Suzuki Takako, Kawano Yoshihiko, Kawada Jun-ichi, Hara Shinya, Saitoh Akihiko, Giske Christian G., Ogi Tomoo, Ito Yoshinori

    OPEN FORUM INFECTIOUS DISEASES   Vol. 9 ( 10 ) page: ofac504   2022.10

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    Background: Infantile central nervous system infections (CNSIs) can be life-threatening and cause severe sequelae. However, the causative microorganism remains unknown in >40% of patients with aseptic infections. This study aimed to analyze the metagenome for detection of pathogens and the transcriptome for host immune responses during infection in a single cerebrospinal fluid (CSF) sample using 2 different next-generation sequencing (NGS) platforms, Nanopore and Illumina. Methods: Twenty-eight CNSIs patients (<12 months) were enrolled, and 49 clinical samples (28 CSF and 21 blood) were collected. The DNA extracted from all 49 samples was sequenced using the Illumina sequencer for the detection of pathogens. Extracted RNA was obtained in sufficient quantities from 23 CSF samples and subjected to sequencing on both Nanopore and Illumina platforms. Human-derived reads subtracted during pathogen detection were used for host transcriptomic analysis from both Nanopore and Illumina sequencing. Results: RNA metagenomic sequencing using both sequencing platforms revealed putative viral pathogens in 10 cases. DNA sequencing using the Illumina sequencer detected 2 pathogens. The results of Nanopore and Illumina RNA sequencing were consistent; however, the mapping coverage and depth to the detected pathogen genome of Nanopore RNA sequencing were greater than those of Illumina. Host transcriptomic analysis of Nanopore sequencing revealed highly expressed genes related to the antiviral roles of innate immunity from pathogen-identified cases. Conclusions: The use of Nanopore RNA sequencing for metagenomic diagnostics of CSF samples should help to elucidate both pathogens and host immune responses of CNSI and could shed light on the pathogenesis of these infections.

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  18. Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis

    Murakami Ayuka, Noda Seiya, Kazuta Tomoyuki, Hirano Satoko, Kimura Seigo, Nakanishi Hirotaka, Matsuo Koji, Tsujikawa Koyo, Iida Madoka, Koike Haruki, Sakamoto Kazuma, Hara Yuichiro, Kuru Satoshi, Kadomatsu Kenji, Shimamura Teppei, Ogi Tomoo, Katsuno Masahisa

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY   Vol. 9 ( 10 ) page: 1602 - 1615   2022.10

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    Objective: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. Methods: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. Results: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. Interpretation: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.

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  19. Six years’ accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures

    Takahashi Y., Date H., Oi H., Adachi T., Imanishi N., Kimura E., Takizawa H., Kosugi S., Matsumoto N., Kosaki K., Matsubara Y., Ando Y., Anzai T., Ariga T., Fukushima Y., Furusawa Y., Ganaha A., Goto Y., Hata K., Honda M., Iijima K., Ikka T., Imoto I., Kaname T., Kobayashi M., Kojima S., Kurahashi H., Kure S., Kurosawa K., Maegaki Y., Makita Y., Morio T., Narita I., Nomura F., Ogata T., Ozono K., Oka A., Okamoto N., Saitoh S., Sakurai A., Takada F., Takahashi T., Tamaoka A., Umezawa A., Yachie A., Yoshiura K., Chinen Y., Eguchi M., Fujio K., Hosoda K., Ichikawa T., Kawarai T., Kosho T., Masuno M., Nakamura A., Nakane T., Ogi T., Okada S., Sakata Y., Seto T., Takahashi Y., Takano T., Ueda M., Yagasaki H., Yamamoto T., Watanabe A., Hotta Y., Kubo A., Maruyama H., Moriyama K., Nanba E., Sakai N., Sekijima Y., Shimosegawa T., Takeuchi T., Usami S., Yamamoto K., Mizusawa H.

    Journal of Human Genetics   Vol. 67 ( 9 ) page: 505 - 513   2022.9

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    The identification of causative genetic variants for hereditary diseases has revolutionized clinical medicine and an extensive collaborative framework with international cooperation has become a global trend to understand rare disorders. The Initiative on Rare and Undiagnosed Diseases (IRUD) was established in Japan to provide accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases. The fundamental IRUD system consists of three pillars: IRUD diagnostic coordination, analysis centers (IRUD-ACs), and a data center (IRUD-DC). IRUD diagnostic coordination consists of clinical centers (IRUD-CLs) and clinical specialty subgroups (IRUD-CSSs). In addition, the IRUD coordinating center (IRUD-CC) manages the entire IRUD system and temporarily operates the IRUD resource center (IRUD-RC). By the end of March 2021, 6301 pedigrees consisting of 18,136 individuals were registered in the IRUD. The whole-exome sequencing method was completed in 5136 pedigrees, and a final diagnosis was established in 2247 pedigrees (43.8%). The total number of aberrated genes and pathogenic variants was 657 and 1718, among which 1113 (64.8%) were novel. In addition, 39 novel disease entities or phenotypes with 41 aberrated genes were identified. The 6-year endeavor of IRUD has been an overwhelming success, establishing an all-Japan comprehensive diagnostic and research system covering all geographic areas and clinical specialties/subspecialties. IRUD has accurately diagnosed diseases, identified novel aberrated genes or disease entities, discovered many candidate genes, and enriched phenotypic and pathogenic variant databases. Further promotion of the IRUD is essential for determining causes and developing cures for rare and undiagnosed diseases.

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  20. A novel ZC4H2 variant in a female with severe respiratory complications

    Wakabayashi Tomohiro, Mizukami Miyako, Terada Kojiro, Ishikawa Aki, Hinotsu Shiro, Kobayashi Masaki, Kato Koji, Ogi Tomoo, Tsugawa Takeshi, Sakurai Akihiro

    BRAIN & DEVELOPMENT   Vol. 44 ( 8 ) page: 571 - 577   2022.9

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    Introduction: An X-linked ZC4H2 variant is associated with a variety of phenotypes that have abnormalities related to external malformation and neurodevelopment. There have been no reports on severe respiratory dysfunction resulting in surgical treatments not being possible due to the deformity resulting from in this disease. Here we report a female with arthrogryposis multiplex congenita with a severe respiratory complication. Case: A two-year-old girl had arthrogryposis multiplex congenita at delivery and subsequently had hypotonia and feeding difficulty. A novel ZC4H2 frameshift variant was identified by whole-exome sequencing in her genome. At eight months, she had recurrent aspiration pneumonia. A tracheostomy and gastrostomy were required; however, surgical intervention was not possible because of her short neck and complicated airway. Conclusion: We compared this case with previous reports. The truncation group had more described phenotypes than the non-truncation group. The patient had the most severe respiratory dysfunction in truncating variant.

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  21. Ceramide profiling of stratum corneum in Sjögren-Larsson syndrome. Reviewed International journal

    Ayami Arai, Takuya Takeichi, Hiroyuki Wakamoto, Takayuki Sassa, Yasutoshi Ito, Yuya Murase, Tomoo Ogi, Masashi Akiyama, Akio Kihara

    Journal of dermatological science   Vol. 107 ( 3 ) page: 114 - 122   2022.9

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    BACKGROUND: Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. OBJECTIVES: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. METHODS: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. RESULTS: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. CONCLUSION: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

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  22. Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

    Narita Kotaro, Muramatsu Hideki, Narumi Satoshi, Nakamura Yuji, Okuno Yusuke, Suzuki Kyogo, Hamada Motoharu, Yamaguchi Naoya, Suzuki Atsushi, Nishio Yosuke, Shiraki Anna, Yamamori Ayako, Tsumura Yusuke, Sawamura Fumi, Kawaguchi Masahiro, Wakamatsu Manabu, Kataoka Shinsuke, Kato Kohji, Asada Hideyuki, Kubota Tetsuo, Muramatsu Yukako, Kidokoro Hiroyuki, Natsume Jun, Mizuno Seiji, Nakata Tomohiko, Inagaki Hidehito, Ishihara Naoko, Yonekawa Takahiro, Okumura Akihisa, Ogi Tomoo, Kojima Seiji, Kaname Tadashi, Hasegawa Tomonobu, Saitoh Shinji, Takahashi Yoshiyuki

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 14589   2022.8

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    Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

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  23. Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

    Kimura Hiroki, Nakatochi Masahiro, Aleksic Branko, Guevara James, Toyama Miho, Hayashi Yu, Kato Hidekazu, Kushima Itaru, Morikawa Mako, Ishizuka Kanako, Okada Takashi, Tsurusaki Yoshinori, Fujita Atsushi, Miyake Noriko, Ogi Tomoo, Takata Atsushi, Matsumoto Naomichi, Buxbaum Joseph, Ozaki Norio, Sebat Jonathan

    TRANSLATIONAL PSYCHIATRY   Vol. 12 ( 1 ) page: 265   2022.7

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    Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10−4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

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  24. The iodide transporter Slc26a7 impacts thyroid function more strongly than Slc26a4 in mice

    Yamaguchi Naoya, Suzuki Atsushi, Yoshida Aya, Tanaka Tatsushi, Aoyama Kohei, Oishi Hisashi, Hara Yuichiro, Ogi Tomoo, Amano Izuki, Kameo Satomi, Koibuchi Noriyuki, Shibata Yasuhiro, Ugawa Shinya, Mizuno Haruo, Saitoh Shinji

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 11259   2022.7

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    SLC26A4 is a known iodide transporter, and is localized at the apical membrane of thyrocytes. Previously, we reported that SLC26A7 is also involved in iodide transport and that Slc26a7 is a novel causative gene for congenital hypothyroidism. However, its detailed role in vivo remains to be elucidated. We generated mice that were deficient in Slc26a7 and Slc26a4 to delineate differences and associations in their roles in iodide transport. Slc26a7−/− mice showed goitrous congenital hypothyroidism and mild growth failure on a normal diet. Slc26a7−/− mice with a low iodine environment showed marked growth failure. In contrast, Slc26a4−/− mice showed no growth failure and hypothyroidism in the same low iodine environment. Double-deficient mice showed more severe growth failure than Slc26a7−/− mice. RNA-seq analysis revealed that the number of differentially expressed genes (DEGs) in Slc26a7−/− mice was significantly higher than that in Slc26a4−/− mice. These indicate that SLC26A7 is more strongly involved in iodide transport and the maintenance of thyroid function than SLC26A4.

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  25. Case of ichthyosis with confetti caused by KRT10 mutation, complicated with multiple malignant melanomas. International journal

    Yasutoshi Ito, Takuya Takeichi, Koichi Nakagawa, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    The Journal of dermatology   Vol. 49 ( 7 ) page: E228 - E229   2022.7

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  26. Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2. International journal

    Yuika Suzuki, Takuya Takeichi, Kana Tanahashi, Yoshinao Muro, Yasushi Suga, Tomoo Ogi, Masashi Akiyama

    International journal of molecular sciences   Vol. 23 ( 14 )   2022.7

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    Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient's age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.

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  27. Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study

    Torii Yuka, Horiba Kazuhiro, Kawada Jun-ichi, Haruta Kazunori, Yamaguchi Makoto, Suzuki Takako, Uryu Hideko, Kashiwa Naoyuki, Goishi Keiji, Ogi Tomoo, Ito Yoshinori

    BMC INFECTIOUS DISEASES   Vol. 22 ( 1 ) page: 568   2022.6

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    Background: Congenital human cytomegalovirus (cCMV) infection can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Ganciclovir and valganciclovir (GCV/VGCV) improve long-term audiologic and neurodevelopmental outcomes for patients with cCMV infection; however, antiviral drug resistance has been documented in some cases. Long-read sequencing can be used for the detection of drug resistance mutations. The objective of this study was to develop full-length analysis of UL97 and UL54, target genes with mutations that confer GCV/VGCV resistance using long-read sequencing, and investigate drug resistance mutation in patients with cCMV infection. Methods: Drug resistance mutation analysis was retrospectively performed in 11 patients with cCMV infection treated with GCV/VGCV. UL97 and UL54 genes were amplified using blood DNA. The amplicons were sequenced using a long-read sequencer and aligned with the reference gene. Single nucleotide variants were detected and replaced with the reference sequence. The replaced sequence was submitted to a mutation resistance analyzer, which is an open platform for drug resistance mutations. Results: Two drug resistance mutations (UL54 V823A and UL97 A594V) were found in one patient. Both mutations emerged after 6 months of therapy, where viral load increased. Mutation rates subsided after cessation of GCV/VGCV treatment. Conclusions: Antiviral drug resistance can emerge in patients with cCMV receiving long-term therapy. Full-length analysis of UL97 and UL54 via long-read sequencing enabled the rapid and comprehensive detection of drug resistance mutations.

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  28. Expanding the phenotypic spectrum of ARCN1-related syndrome

    Ritter Alyssa L., Gold Jessica, Hayashi Hiroshi, Ackermann Amanda M., Hanke Stephanie, Skraban Cara, Cuddapah Sanmati, Bhoj Elizabeth, Li Dong, Kuroda Yukiko, Wen Jessica, Takeda Ryojun, Bibb Audrey, El Chehadeh Salima, Piton Amelie, Ohl Jeanine, Kukolich Mary K., Nagasaki Keisuke, Kato Kohji, Ogi Tomoo, Bhatti Tricia, Russo Pierre, Krock Bryan, Murrell Jill R., Sullivan Jennifer A., Shashi Vandana, Stong Nicholas, Hakonarson Hakon, Sawano Kentaro, Torti Erin, Willaert Rebecca, Si Yue, Wilcox William Ross, Wirgenes Katrine Verena, Thomassen Kristian, Carlotti Katherine, Erwin Angelika, Lazier Joanna, Marquardt Thorsten, He Miao, Edmondson Andrew C., Izumi Kosuke

    GENETICS IN MEDICINE   Vol. 24 ( 6 ) page: 1227 - 1237   2022.6

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    Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. Results: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. Conclusion: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.

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  29. 経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

    有沢 友希, 武市 拓也, 伊藤 靖敏, 棚橋 華奈, 室 慶直, 荻 朋男, 秋山 真志

    加齢皮膚医学セミナー   Vol. 17 ( 1 ) page: 74 - 75   2022.6

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  30. 経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

    有沢 友希, 武市 拓也, 伊藤 靖敏, 棚橋 華奈, 室 慶直, 荻 朋男, 秋山 真志

    加齢皮膚医学セミナー   Vol. 17 ( 1 ) page: 74 - 75   2022.6

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  31. Epithelioid cell granuloma formation in CARD14-associated papulosquamous eruptions. International journal

    Takuya Takeichi, Kenta Ikeda, Yoshinao Muro, Tomoo Ogi, Shin Morizane, Masashi Akiyama

    Journal of the European Academy of Dermatology and Venereology : JEADV   Vol. 36 ( 5 ) page: E369 - E371   2022.5

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  32. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

    Stephenson Sarah E. M., Costain Gregory, Blok Laura E. R., Silk Michael A., Nguyen Thanh Binh, Dong Xiaomin, Alhuzaimi Dana E., Dowling James J., Walker Susan, Amburgey Kimberly, Hayeems Robin Z., Rodan Lance H., Schwartz Marc A., Picker Jonathan, Lynch Sally A., Gupta Aditi, Rasmussen Kristen J., Schimmenti Lisa A., Klee Eric W., Niu Zhiyv, Agre Katherine E., Chilton Ilana, Chung Wendy K., Revah-Politi Anya, Au P. Y. Billie, Griffith Christopher, Racobaldo Melissa, Raas-Rothschild Annick, Ben Zeev Bruria, Barel Ortal, Moutton Sebastien, Morice-Picard Fanny, Carmignac Virginie, Cornaton Jenny, Marle Nathalie, Devinsky Orrin, Stimach Chandler, Wechsler Stephanie Burns, Hainline Bryan E., Sapp Katie, Willems Marjolaine, Bruel Angeline, Dias Kerith-Rae, Evans Carey-Anne, Roscioli Tony, Sachdev Rani, Temple Suzanna E. L., Zhu Ying, Baker Joshua J., Scheffer Ingrid E., Gardiner Fiona J., Schneider Amy L., Muir Alison M., Mefford Heather C., Crunk Amy, Heise Elizabeth M., Millan Francisca, Monaghan Kristin G., Person Richard, Rhodes Lindsay, Richards Sarah, Wentzensen Ingrid M., Cogne Benjamin, Isidor Bertrand, Nizon Mathilde, Vincent Marie, Besnard Thomas, Piton Amelie, Marcelis Carlo, Kato Kohji, Koyama Norihisa, Ogi Tomoo, Goh Elaine Suk-Ying, Richmond Christopher, Amor David J., Boyce Jessica O., Morgan Angela T., Hildebrand Michael S., Kaspi Antony, Bahlo Melanie, Fridriksdottir Run, Katrinardottir Hildigunnur, Sulem Patrick, Stefansson Kari, Bjornsson Hans Tomas, Mandelstam Simone, Morleo Manuela, Mariani Milena, Scala Marcello, Accogli Andrea, Torella Annalaura, Capra Valeria, Wallis Mathew, Jansen Sandra, Waisfisz Quinten, de Haan Hugoline, Sadedin Simon, Lim Sze Chern, White Susan M., Ascher David B., Schenck Annette, Lockhart Paul J., Christodoulou John, Tan Tiong Yang

    AMERICAN JOURNAL OF HUMAN GENETICS   Vol. 109 ( 4 ) page: 601 - 617   2022.4

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    Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

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  33. Mutations in SAM syndrome and palmoplantar keratoderma patients suggest genotype/phenotype correlations in DSG1 mutations

    Takeuchi S., Takeichi T., Koike Y., Takama H., Tanahashi K., Okuno Y., Ishii N., Muro Y., Ogi T., Suga Y., Akiyama M.

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY   Vol. 36 ( 3 ) page: E215 - E218   2022.3

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  34. Clinical practice guidelines for pseudoxanthoma elasticum (2017): Clinical Practice Guidelines for Pseudoxanthoma Elasticum Drafting Committee: Clinical Practice Guidelines for Pseudoxanthoma Elasticum Drafting Committee. International journal

    Akira Iwanaga, Atsushi Utani, Yuta Koike, Yumi Okubo, Yutaka Kuwatsuka, Yuichiro Endo, Hideaki Tanizaki, Mari Wataya-Kaneda, Atsushi Hatamochi, Kosuke Minaga, Tomoo Ogi, Yosuke Yamamoto, Satoshi Ikeda, Eiko Tsuiki, Hiroshi Tamura, Koji Maemura, Takashi Kitaoka, Hiroyuki Murota

    The Journal of dermatology   Vol. 49 ( 3 ) page: e91-e98 - e98   2022.1

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    Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease that affects tissues such as the skin, retina, blood vessels, and gastrointestinal tracts. Therefore, comprehensive medical care across clinical departments specialized in specific organs is needed to provide the best clinical practices to PXE patients. The Japanese version of clinical guidelines developed by the Japanese Dermatological Association was published in 2017, and aimed to promote equal accessibility of PXE-related medical care. Here, the English version of Japanese guideline is reported, and is intended to be worldwide reference for medical care of PXE.

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  35. Subtle infantile spasms presenting as hyperirritability in CK syndrome

    Hagiwara Sho, Shiohama Tadashi, Ogi Tomoo, Ichikawa Tomohiko, Hamada Hiromichi

    PEDIATRICS INTERNATIONAL   Vol. 64 ( 1 ) page: e15335   2022.1

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  36. Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels

    Toyama Miho, Takasaki Yuto, Branko Aleksic, Kimura Hiroki, Kato Hidekazu, Nawa Yoshihiro, Kushima Itaru, Ishizuka Kanako, Shimamura Teppei, Ogi Tomoo, Ozaki Norio

    PLOS ONE   Vol. 17 ( 5 ) page: e0268321   2022

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    Background Most sequencing studies of schizophrenia (SCZ) have focused on de novo genetic variants due to interpretability. However, investigating shared rare variants among patients in the same multiplex family is also important. Relatively large-scale analyses of SCZ multiplex families have been done in Caucasian populations, but whether detected variants are also pathogenic in the Japanese population is unclear because of ethnic differences in rare variants. Materials and methods We performed whole-exome sequencing (WES) of 14 Japanese SCZ multiplex families. After quality control and filtering, we identified rare variants shared among affected persons within the same family. A gene ontology (GO) analysis was performed to identify gene categories possibly affected by these candidate variants. Results We found 530 variants in 486 genes as potential candidate variants from the 14 SCZ multiplex families examined. The GO analysis demonstrated significant enrichment in calcium channel activity. Conclusion This study provides supporting evidence that calcium ion channel activity is involved in SCZ. WES of multiplex families is a potential means of identifying disease-associated rare variants for SCZ.

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  37. Next-Generation Sequencing to Detect Pathogens in Pediatric Febrile Neutropenia: A Single-Center Retrospective Study of 112 Cases

    Kazuhiro Horiba, Yuka Torii, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Hideki Muramatsu, Yoshiyuki Takahashi, Tomoo Ogi, Yoshinori Ito

    Open Forum Infectious Diseases   Vol. 8 ( 11 ) page: ofab223   2021.11

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    <title>Abstract</title>
    <sec>
    <title>Background</title>
    Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to idenjpgy the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN.


    </sec>
    <sec>
    <title>Methods</title>
    FN is defined as 1) a neutrophil count &amp;lt; 500/µL, and 2) fever ≥ 37.5 °C. Plasma/serum samples of 112 pediatric patients with FN, 10 patients with neutropenia without fever (NE), were sequenced by NGS and analyzed by a metagenomic pipeline PATHDET.


    </sec>
    <sec>
    <title>Results</title>
    The putative pathogens were detected by NGS in 5 of 10 patients with FN with positive for blood culture results, 15 of 87 patients (17%) with negative for blood culture results, and 3 of 8 patients with NE. Several bacteria that were common in the oral, skin, and gut flora were commonly detected in blood samples, suggesting translocation of the human microbiota to the bloodstream in the setting of neutropenia. The cluster analysis of the microbiota in blood samples using NGS demonstrated that the representative bacteria of each cluster was mostly consistent with the pathogens in each patient.


    </sec>
    <sec>
    <title>Conclusions</title>
    NGS technique has a great potential for detecting causative pathogens in patients with FN. Cluster analysis, which extracts characteristic microorganisms from a complex microbial population, may be effective to detect pathogens in minute quantities of microbiota, such as those from the bloodstream.


    </sec>

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  38. Extensive multiple organ involvement in VEXAS syndrome

    Noriyuki Takahashi, Takuya Takeichi, Tetsuya Nishida, Yasuhiro Takahashi, Juichi Sato, Masahiro Yamamura, Tomoo Ogi, Masashi Akiyama

    Arthritis & Rheumatology   Vol. 73 ( 10 ) page: 1896 - 1897   2021.10

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  39. Dealing with transcription-blocking DNA damage: Repair mechanisms, RNA polymerase II processing and human disorders

    Jia Nan, Guo Chaowan, Nakazawa Yuka, Heuvel Diana van den, Luijsterburg Martijn S., Ogi Tomoo

    DNA REPAIR   Vol. 106   page: 103192   2021.10

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    Transcription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and fully block transcription when unresolved. The toxic impact of DNA damage on transcription progression is commonly referred to as transcription stress. In response to RNA Pol II stalling, cells activate and employ transcription-coupled repair (TCR) machineries to repair cytotoxic TBLs and resume transcription. Increasing evidence indicates that the modification and processing of stalled RNA Pol II is an integral component of the cellular response to and the repair of TBLs. If TCR pathways fail, the prolonged stalling of RNA Pol II will impede global replication and transcription as well as block the access of other DNA repair pathways that may act upon the TBL. Consequently, such prolonged stalling will trigger profound genome instability and devastating clinical features. In this review, we will discuss the mechanisms by which various types of TBLs are repaired by distinct TCR pathways and how RNA Pol II processing is regulated during these processes. We will also discuss the clinical consequences of transcription stress and genotype-phenotype correlations of related TCR-deficiency disorders.

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  40. Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome

    Murase C., Takeichi T., Taki T., Yoshikawa T., Suzuki A., Ogi T., Suga Y., Akiyama M.

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 141 ( 10 ) page: S177 - S177   2021.10

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  41. Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

    Botta Elena, Theil Arjan F., Raams Anja, Caligiuri Giuseppina, Giachetti Sarah, Bione Silvia, Accadia Maria, Lombardi Anita, Smith Desiree E. C., Mendes Marisa I, Swagemakers Sigrid M. A., Van der Spek Peter J., Salomons Gajja S., Hoeijmakers Jan H. J., Yesodharan Dhanya, Nampoothiri Sheela, Ogi Tomoo, Lehmann Alan R., Orioli Donata, Vermeulen Wim

    HUMAN MOLECULAR GENETICS   Vol. 30 ( 18 ) page: 1711 - 1720   2021.9

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    Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulfur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) forms exhibits in addition to progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD. These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasize this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription redefines TTD as a syndrome in which proteins involved in gene expression are unstable.

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  42. Cutaneous malignant melanoma in an elderly patient with intermediate junctional epidermolysis bullosa. International journal

    Yuta Yamashita, Tomoki Taki, Takuya Takeichi, Mao Okumura, Shoichiro Mori, Yasutoshi Ito, Tomoo Ogi, Motohito Yamada, Masashi Akiyama

    The Journal of dermatology   Vol. 48 ( 8 ) page: E384 - E385   2021.8

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  43. The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model

    Yoshioka Naoki, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Ono Kenji, Sawada Makoto, Ogi Tomoo, Itoh Michiko, Ito Ayaka, Shiraki Yukihiro, Enomoto Atsushi, Ishigami Masatoshi, Fujishiro Mitsuhiro, Ogawa Yoshihiro, Suganami Takayoshi

    BIOMEDICINE & PHARMACOTHERAPY   Vol. 140   page: 111738   2021.8

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    Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

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  44. Updated allele frequencies of SERPINB7 founder mutations in Asian patients with Nagashima-type palmoplantar keratosis/keratoderma

    Yasutoshi Ito, Takuya Takeichi, Kenta Ikeda, Kana Tanahashi, Takenori Yoshikawa, Yuya Murase, Yoshinao Muro, Yoshio Kawakami, Yasuo Nakamura, Kanako Matsuyama, Jun Muto, Naoki Oiso, Shin Morizane, Kazumitsu Sugiura, Yasushi Suga, Mariko Seishima, Akira Kawada, Tomoo Ogi, Masashi Akiyama

    Journal of Dermatological Science   Vol. 103 ( 2 ) page: 116 - 119   2021.8

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    DOI: 10.1016/j.jdermsci.2021.06.002

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  45. Paradoxical Reaction in a Patient with Hidradenitis Suppurativa Undergoing Adalimumab Treatment. International journal

    Soichiro Ikeya, Takuya Takeichi, Tomoki Taki, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    Acta dermato-venereologica   Vol. 101 ( 6 ) page: adv00484   2021.6

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    DOI: 10.2340/00015555-3844

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  46. Pediatric sepsis cases diagnosed with group B streptococcal meningitis using next-generation sequencing: a report of two cases

    Horiba Kazuhiro, Suzuki Michio, Tetsuka Nobuyuki, Kawano Yoshihiko, Yamaguchi Makoto, Okumura Toshihiko, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Morita Makoto, Hara Shinya, Ogi Tomoo, Ito Yoshinori

    BMC INFECTIOUS DISEASES   Vol. 21 ( 1 ) page: 531   2021.6

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    Background: Group B Streptococcus (GBS) is an important cause of invasive infection in neonates and infants. Cerebrospinal fluid (CSF) findings and culture may not show evidence of infection early in GBS meningitis. Next-generation sequencing (NGS) has the potential to detect microbial genetic material in patients with infectious diseases. We report two cases of infantile sepsis of GBS meningitis with negative results for CSF culture tests, but positive results for NGS analysis. Case presentation: Patient 1 was a 22-day-old male infant diagnosed with sepsis and meningitis. His CSF findings showed pleocytosis, decreased glucose, and increased protein levels. However, CSF and blood culture results at admission were negative. He received a total of 3 weeks of treatment with ampicillin and cefotaxime, and showed clinical improvement. GBS was detected through NGS analysis of CSF collected at admission. Patient 2 was a 51-day-old male infant with sepsis. CSF findings on admission were normal, and blood and CSF cultures were also negative. Intravenous ampicillin and cefotaxime treatment were initiated. Treatment was de-escalated to ampicillin alone because Enterococcus faecalis was cultured from urine. He was discharged after a total of 1 week of antibiotic treatment. Six days after discharge, he was re-hospitalized for sepsis. Blood and CSF cultures were negative, and E. faecalis was again cultured from urine. He received a total of 3 weeks of ampicillin treatment for enterococcal-induced nephritis and did not relapse thereafter. NGS pathogen searches were retrospectively performed on both blood and CSF collected at the first and second admission. GBS was detected in the CSF collected at the first admission, but no significant pathogen was detected in the other samples. Inadequate treatment for GBS meningitis at the first admission may have caused the recurrence of the disease. Conclusion: Infantile sepsis may present bacterial meningitis that is not diagnosed by either culture testing or CSF findings. NGS analysis for CSF may be useful for confirming the diagnosis of bacterial meningitis.

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  47. Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder

    Jiang Wenjun, Jia Nan, Guo Chaowan, Wen Juan, Wu Lingqian, Ogi Tomoo, Zhang Huiwen

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE   Vol. 1867 ( 6 ) page: 166106   2021.6

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    TOP3A promotes processing of double Holliday junction dissolution and also plays an important role in decatenation and segregation of human mtDNA. Recently, TOP3A mutations have been reported to cause Bloom syndrome-like disorder. However, whether the two function play equal roles in the disease pathogenesis is unclear. We retrospectively studied the disease progression of two siblings with Bloom-like syndrome caused by two novel mutations of TOP3A, p.Q788* and p.D479G. Beside the common clinical manifestations, our patients exhibited liver lipid storage with hepatomegaly. In cellular and molecular biological studies, TOP3A deficiency moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency. These changes were rescued by ectopic expression of either of the wildtype TOP3A or TOP3A-D479G. In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G. Considering the different impact of the TOP3A-D479G mutation on the genome stability and mitochondrial metabolism, we propose that the impaired mitochondrial metabolism plays an important role in the pathogenesis of TOP3A-deficient Bloom-like disease.

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  48. Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants. International journal

    Chiaki Murase, Takuya Takeichi, Toshifumi Nomura, Tomoo Ogi, Masashi Akiyama

    The Journal of investigative dermatology   Vol. 141 ( 6 ) page: 1596 - 1598   2021.6

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  49. ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation. International journal

    Yana van der Weegen, Klaas de Lint, Diana van den Heuvel, Yuka Nakazawa, Tycho E T Mevissen, Janne J M van Schie, Marta San Martin Alonso, Daphne E C Boer, Román González-Prieto, Ishwarya V Narayanan, Noud H M Klaassen, Annelotte P Wondergem, Khashayar Roohollahi, Josephine C Dorsman, Yuichiro Hara, Alfred C O Vertegaal, Job de Lange, Johannes C Walter, Sylvie M Noordermeer, Mats Ljungman, Tomoo Ogi, Rob M F Wolthuis, Martijn S Luijsterburg

    Nature cell biology   Vol. 23 ( 6 ) page: 595 - 607   2021.6

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    Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4CSA ubiquitin ligase. How CRL4CSA is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4CSA for optimal RNAPII ubiquitylation. Drug-genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.

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  50. Transcription-Coupled DNA Repair: From Mechanism to Human Disorder

    van den Heuvel Diana, van der Weegen Yana, Boer Daphne E. C., Ogi Tomoo, Luijsterburg Martijn S.

    TRENDS IN CELL BIOLOGY   Vol. 31 ( 5 ) page: 359 - 371   2021.5

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    DNA lesions pose a major obstacle during gene transcription by RNA polymerase II (RNAPII) enzymes. The transcription-coupled DNA repair (TCR) pathway eliminates such DNA lesions. Inherited defects in TCR cause severe clinical syndromes, including Cockayne syndrome (CS). The molecular mechanism of TCR and the molecular origin of CS have long remained enigmatic. Here we explore new advances in our understanding of how TCR complexes assemble through cooperative interactions between repair factors stimulated by RNAPII ubiquitylation. Mounting evidence suggests that RNAPII ubiquitylation activates TCR complex assembly during repair and, in parallel, promotes processing and degradation of RNAPII to prevent prolonged stalling. The fate of stalled RNAPII is therefore emerging as a crucial link between TCR and associated human diseases.

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  51. Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome. International journal

    Chiaki Murase, Takuya Takeichi, Tomoki Taki, Takenori Yoshikawa, Akiko Suzuki, Tomoo Ogi, Yasushi Suga, Masashi Akiyama

    Journal of dermatological science   Vol. 102 ( 2 ) page: 126 - 129   2021.5

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  52. MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1

    Ito Y., Takeichi T., Igari S., Mori T., Ono A., Suyama K., Takeuchi S., Muro Y., Ogi T., Hosoya M., Yamamoto T., Akiyama M.

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY   Vol. 35 ( 5 ) page: E345 - E347   2021.5

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  53. Odontogenic keratocysts are an important clue for diagnosing basal cell nevus syndrome.

    Kaori Kaibuchi-Ando, Takuya Takeichi, Yasutoshi Ito, So Takeuchi, Yuta Yamashita, Motohito Yamada, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    Nagoya journal of medical science   Vol. 83 ( 2 ) page: 393 - 396   2021.5

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    Basal cell nevus syndrome (BCNS) is an autosomal dominant skin disorder characterized by multiple basal cell nevi. Patients with BCNS tend to develop basal cell carcinoma (BCC) and frequently show skeletal abnormalities. Most cases of BCNS are caused by mutations in patched 1 (PTCH1). PTCH1 encodes a transmembrane receptor protein for the secreted molecule sonic hedgehog, which plays a key role in the development of animals ranging from insects to mammals. We analyzed two Japanese BCNS patients from two independent families. Both of our patients had multiple jaw keratocysts. In one patient, these were the key to noticing his BCNS, as he had no skin tumors. The early detection of PTCH1 mutations would enable BCNS patients to be carefully followed up for the occurrence of BCC. The diagnosis of BCC at the early stage leads to prompt surgical treatments, resulting in a good prognosis. The present cases suggest that keratocysts of the jaw might be an important clue for diagnosing BCNS.

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  54. [A case of Charcot-Marie-Tooth disease type 2Z caused by MORC2 S87L mutation mimicking spinal muscular atrophy].

    Yamamoto D, Oda R, Hisahara S, Ishikawa A, Ogi T, Shimohama S

    Rinsho shinkeigaku = Clinical neurology   Vol. 61 ( 4 ) page: 262 - 264   2021.4

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    A 33-year-old man with an unremarkable family history has had limb muscle weakness, joint contracture and skeleton deformation from early childhood. He was diagnosed with spinal muscular atrophy (SMA) by a pediatrician. He needed assistance and used orthoses in his daily life. There was no subjective sensory disturbance. However, physical examination showed slight sensory impairment, and nerve conduction study indicated sensory motor axonal neuropathy. This finding suggested Charcot-Marie-Tooth disease (CMT). Gene analysis detected MORC2 S87L mutation, leading to a diagnosis of CMT type 2Z. Patients with MORC2 S87L mutation are known to exhibit a severe phenotype, and may mimic SMA. It is important to demonstrate subclinical sensory neuropathy in patients with MORC2 S87L mutation mimicking SMA.

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  55. Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study

    Okumura Toshihiko, Horiba Kazuhiro, Kamei Hideya, Takeuchi Suguru, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Takahashi Yoshiyuki, Ogura Yasuhiro, Ogi Tomoo, Ito Yoshinori

    BMC MICROBIOLOGY   Vol. 21 ( 1 ) page: 104   2021.4

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    Background: Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events. Results: In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition. Conclusions: The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.

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  56. The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy. International journal

    Takashi Ando, Ryoichi Nakamura, Satoshi Kuru, Daichi Yokoi, Naoki Atsuta, Haruki Koike, Masashi Suzuki, Kazuhiro Hara, Yohei Iguchi, Yumiko Harada, Yusuke Yoshida, Makoto Hattori, Ayuka Murakami, Seiya Noda, Seigo Kimura, Jun Sone, Tomohiko Nakamura, Yoji Goto, Kazuo Mano, Hisashi Okada, Satoshi Okuda, Ichizo Nishino, Tomoo Ogi, Gen Sobue, Masahisa Katsuno

    Neurobiology of aging   Vol. 100   page: 120.e1 - 120.e6   2021.4

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    Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

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  57. Two Cases of Porokeratosis with MVD Mutations, in Association with Bullous Pemphigoid. International journal

    Yuki Arisawa, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Takuya Takeichi, Masashi Akiyama

    Acta dermato-venereologica   Vol. 101 ( 3 ) page: adv00423   2021.3

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  58. Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing. International journal

    So Takeuchi, Takuya Takeichi, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    European journal of dermatology : EJD   Vol. 31 ( 2 ) page: 264 - 265   2021.3

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  59. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease. International journal

    Akira Sobue, Okiru Komine, Yuichiro Hara, Fumito Endo, Hiroyuki Mizoguchi, Seiji Watanabe, Shigeo Murayama, Takashi Saito, Takaomi C Saido, Naruhiko Sahara, Makoto Higuchi, Tomoo Ogi, Koji Yamanaka

    Acta neuropathologica communications   Vol. 9 ( 1 ) page: 1 - 1   2021.1

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    Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

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  60. Expanding the phenotype of biallelic loss-of-function variants in the NSUN2 gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications. International journal

    Kohji Kato, Seiji Mizuno, Jenny Morton, Miho Toyama, Yuichiro Hara, Evangeline Wasmer, Alan Lehmann, Tomoo Ogi

    American journal of medical genetics. Part A   Vol. 185 ( 1 ) page: 282 - 285   2021.1

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    The NSUN2 gene encodes a tRNA cytosine methyltransferase that functions in the maturation of leucyl tRNA (Leu) (CAA) precursors, which is crucial for the anticodon-codon pairing and correct translation of mRNA. Biallelic loss of function variants in NSUN2 are known to cause moderate to severe intellectual disability. Microcephaly, postnatal growth retardation, and dysmorphic facial features are common complications in this genetic disorder, and delayed puberty is occasionally observed. Here, we report four individuals, two sets of siblings, with biallelic loss-of-function variants in the NSUN2 gene. The first set of siblings have compound heterozygous frameshift variants: c.546_547insCT, p.Met183Leufs*13; c.1583del, p.Pro528Hisfs*19, and the other siblings carry a homozygous frameshift variant: c.1269dup, p.Val424Cysfs*14. In addition to previously reported clinical features, the first set of siblings showed novel complications of juvenile cataract and chronic nephritis. The other siblings showed hypomyelination and simplified gyral pattern in neuroimaging. NSUN2-related intellectual disability is a very rare condition, and less than 20 cases have been reported previously. Juvenile cataract, chronic nephritis, and brain anomaly shown in the present patients have not been previously described. Our report suggests clinical diversity of NSUN2-related intellectual disability.

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  61. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

    Yasuyoshi Oka, Motoharu Hamada, Yuka Nakazawa, Hideki Muramatsu, Yusuke Okuno, Koichiro Higasa, Mayuko Shimada, Honoka Takeshima, Katsuhiro Hanada, Taichi Hirano, Toshiro Kawakita, Hirotoshi Sakaguchi, Takuya Ichimura, Shuichi Ozono, Kotaro Yuge, Yoriko Watanabe, Yuko Kotani, Mutsumi Yamane, Yumiko Kasugai, Miyako Tanaka, Takayoshi Suganami, Shinichiro Nakada, Norisato Mitsutake, Yuichiro Hara, Kohji Kato, Seiji Mizuno, Noriko Miyake, Yosuke Kawai, Katsushi Tokunaga, Masao Nagasaki, Seiji Kito, Keiichi Isoyama, Masafumi Onodera, Hideo Kaneko, Naomichi Matsumoto, Fumihiko Matsuda, Keitaro Matsuo, Yoshiyuki Takahashi, Tomoji Mashimo, Seiji Kojima, Tomoo Ogi

    Science Advances   Vol. 6 ( 51 ) page: eabd7197 - eabd7197   2020.12

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    Rs671 in the aldehyde dehydrogenase 2 gene (<italic>ALDH2</italic>) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (<italic>ADH5<sup>FDH</sup></italic>), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, <italic>Adh5<sup>−/−</sup>Aldh2</italic><sup>E506K/E506K</sup> double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

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  62. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction. International journal

    Hiroyuki Konishi, Takayuki Okamoto, Yuichiro Hara, Okiru Komine, Hiromi Tamada, Mitsuyo Maeda, Fumika Osako, Masaaki Kobayashi, Akira Nishiyama, Yosky Kataoka, Toshiyuki Takai, Nobuyuki Udagawa, Steffen Jung, Keiko Ozato, Tomohiko Tamura, Makoto Tsuda, Koji Yamanaka, Tomoo Ogi, Katsuaki Sato, Hiroshi Kiyama

    The EMBO journal   Vol. 39 ( 22 ) page: e104464   2020.11

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    Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is impaired. We addressed this question using Siglechdtr mice, which enable highly specific ablation of microglia. Non-microglial mononuclear phagocytes, such as CNS-associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro-inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed in Irf8-deficient mice, in which microglia were present but dysfunctional. RNA-seq demonstrated that even in a healthy CNS, astrocytes express TAM phagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthy CNS.

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  63. A heterozygous SERPINB7 mutation is a possible modifying factor for epidermolytic palmoplantar keratoderma. International journal

    Takenori Yoshikawa, Takuya Takeichi, Tomoo Ogi, Yasushi Suga, Yoshinao Muro, Masashi Akiyama

    Journal of dermatological science   Vol. 100 ( 2 ) page: 148 - 151   2020.11

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  64. Comprehensive pathogen detection in sera of Kawasaki disease patients by high-throughput sequencing: a retrospective exploratory study

    Torii Yuka, Horiba Kazuhiro, Hayano Satoshi, Kato Taichi, Suzuki Takako, Kawada Jun-ichi, Takahashi Yoshiyuki, Kojima Seiji, Okuno Yusuke, Ogi Tomoo, Ito Yoshinori

    BMC PEDIATRICS   Vol. 20 ( 1 ) page: 482   2020.10

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    DOI: 10.1186/s12887-020-02380-7

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  65. Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle. International journal

    Kun Huang, Jin Li, Mikako Ito, Jun-Ichi Takeda, Bisei Ohkawara, Tomoo Ogi, Akio Masuda, Kinji Ohno

    Frontiers in molecular neuroscience   Vol. 13   page: 154 - 154   2020.9

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    The neuromuscular junction (NMJ) is a prototypic chemical synapse between the spinal motor neuron and the motor endplate. Gene expression profiles of the motor endplate are not fully elucidated. Collagen Q (ColQ) is a collagenic tail subunit of asymmetric forms of acetylcholinesterase and is driven by two distinct promoters. pColQ1 is active throughout the slow-twitch muscle, whereas pColQ1a is active at the motor endplate of fast-twitch muscle. We made a transgenic mouse line that expresses nuclear localization signal (NLS)-attached Cre recombinase under the control of pColQ1a (pColQ1a-Cre mouse). RiboTag mouse expresses an HA-tagged ribosomal subunit, RPL22, in cells expressing Cre recombinase. We generated pColQ1a-Cre:RiboTag mouse, and confirmed that HA-tagged RPL22 was enriched at the NMJ of tibialis anterior (TA) muscle. Next, we confirmed that Chrne and Musk that are specifically expressed at the NMJ were indeed enriched in HA-immunoprecipitated (IP) RNA, whereas Sox10 and S100b, markers for Schwann cells, and Icam1, a marker for vascular endothelial cells, and Pax3, a marker for muscle satellite cells, were scarcely detected. Gene set enrichment analysis (GSEA) of RNA-seq data showed that "phosphatidylinositol signaling system" and "extracellular matrix receptor interaction" were enriched at the motor endplate. Subsequent analysis revealed that genes encoding diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, and laminins were enriched at the motor endplate. We first characterized the gene expression profile under translation at the motor endplate of TA muscle using the RiboTag technique. We expect that our gene expression profiling will help elucidate molecular mechanisms of the development, maintenance, and pathology of the NMJ.

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  66. NUS1 mutation in a family with epilepsy, cerebellar ataxia, and tremor. Reviewed International journal

    Kunihiko Araki, Ryoichi Nakamura, Daisuke Ito, Kohji Kato, Yohei Iguchi, Kentaro Sahashi, Miho Toyama, Kensuke Hamada, Nobuhiko Okamoto, Yoshinao Wada, Tomohiko Nakamura, Tomoo Ogi, Masahisa Katsuno

    Epilepsy research   Vol. 164   page: 106371 - 106371   2020.8

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    We report on familial 5 epilepsy patients with autosomal dominant inheritance of a novel heterozygous NUS1 frameshift mutation. All patients had cerebellar ataxia and tremor. Three patients were diagnosed with childhood absence epilepsy, 1 patient with generalized epilepsy, and 1 patient with parkinsonism without epilepsy. Our cases and previously reported cases with deletions of chromosome 6q22 that include NUS1 share these common symptoms. In a cellular experiment, NUS1 mutation led to a substantial reduction of the protein level of NUS1. NUS1 mutation could contribute to epilepsy pathogenesis and also constitute a distinct syndromic entity with cerebellar ataxia and tremor.

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  67. Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells. Reviewed International journal

    Liton Kumar Saha, Mitsuo Wakasugi, Salma Akter, Rajendra Prasad, Samuel H Wilson, Naoto Shimizu, Hiroyuki Sasanuma, Shar-Yin Naomi Huang, Keli Agama, Yves Pommier, Tsukasa Matsunaga, Kouji Hirota, Shigenori Iwai, Yuka Nakazawa, Tomoo Ogi, Shunichi Takeda

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 117 ( 25 ) page: 14412 - 14420   2020.6

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    Nucleotide excision repair (NER) removes helix-destabilizing adducts including ultraviolet (UV) lesions, cyclobutane pyrimidine dimers (CPDs), and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). In comparison with CPDs, 6-4PPs have greater cytotoxicity and more strongly destabilizing properties of the DNA helix. It is generally believed that NER is the only DNA repair pathway that removes the UV lesions as evidenced by the previous data since no repair of UV lesions was detected in NER-deficient skin fibroblasts. Topoisomerase I (TOP1) constantly creates transient single-strand breaks (SSBs) releasing the torsional stress in genomic duplex DNA. Stalled TOP1-SSB complexes can form near DNA lesions including abasic sites and ribonucleotides embedded in chromosomal DNA. Here we show that base excision repair (BER) increases cellular tolerance to UV independently of NER in cancer cells. UV lesions irreversibly trap stable TOP1-SSB complexes near the UV damage in NER-deficient cells, and the resulting SSBs activate BER. Biochemical experiments show that 6-4PPs efficiently induce stable TOP1-SSB complexes, and the long-patch repair synthesis of BER removes 6-4PPs downstream of the SSB. Furthermore, NER-deficient cancer cell lines remove 6-4PPs within 24 h, but not CPDs, and the removal correlates with TOP1 expression. NER-deficient skin fibroblasts weakly express TOP1 and show no detectable repair of 6-4PPs. Remarkably, the ectopic expression of TOP1 in these fibroblasts led them to completely repair 6-4PPs within 24 h. In conclusion, we reveal a DNA repair pathway initiated by TOP1, which significantly contributes to cellular tolerance to UV-induced lesions particularly in malignant cancer cells overexpressing TOP1.

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  68. InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution

    Jun-ichi Takeda, Kentaro Nanatsue, Ryosuke Yamagishi, Mikako Ito, Nobuhiko Haga, Hiromi Hirata, Tomoo Ogi, Kinji Ohno

    NAR Genomics and Bioinformatics   Vol. 2 ( 2 ) page: lqaa038   2020.6

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    <title>Abstract</title>
    In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

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  69. Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. Reviewed International journal

    Yuka Nakazawa, Yuichiro Hara, Yasuyoshi Oka, Okiru Komine, Diana van den Heuvel, Chaowan Guo, Yasukazu Daigaku, Mayu Isono, Yuxi He, Mayuko Shimada, Kana Kato, Nan Jia, Satoru Hashimoto, Yuko Kotani, Yuka Miyoshi, Miyako Tanaka, Akira Sobue, Norisato Mitsutake, Takayoshi Suganami, Akio Masuda, Kinji Ohno, Shinichiro Nakada, Tomoji Mashimo, Koji Yamanaka, Martijn S Luijsterburg, Tomoo Ogi

    Cell   Vol. 180 ( 6 ) page: 1228 - +   2020.3

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    Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase II (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIo in response to DNA damage is an evolutionarily conserved event, but its function in mammals is unknown. Here, we identified a single DNA damage-induced ubiquitination site in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damage resistance. Mechanistically, RPB1-K1268 ubiquitination stimulates the association of the core-TFIIH complex with stalled RNAPIIo through a transfer mechanism that also involves UVSSA-K414 ubiquitination. We developed a strand-specific ChIP-seq method, which revealed RPB1-K1268 ubiquitination is important for repair and the resolution of transcriptional bottlenecks at DNA lesions. Finally, RPB1-K1268R knockin mice displayed a short life-span, premature aging, and neurodegeneration. Our results reveal RNAPII ubiquitination provides a two-tier protection mechanism by activating TC-NER and, in parallel, the processing of DNA damage-stalled RNAPIIo, which together prevent prolonged transcription arrest and protect against neurodegeneration.

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  70. Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report. Reviewed International journal

    Tadashi Nagata, Masaki Matsushita, Kenichi Mishima, Yasunari Kamiya, Kohji Kato, Miho Toyama, Tomoo Ogi, Naoki Ishiguro, Hiroshi Kitoh

    Molecular genetics & genomic medicine   Vol. 8 ( 3 ) page: e1148   2020.3

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    BACKGROUND: Achondroplasia (ACH), the most common form of short-limbed skeletal dysplasia, is caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the FGFR3 gene. We present here a child who had two de novo variants in the FGFR3 on the same allele, a common p.G380R mutation and a novel p.S378N variant. METHODS: A 3-year-old Japanese girl born from non-consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short-limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole-exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing. RESULTS: Mutation analysis demonstrated that the proband had p.S378N (c.1133G>A) and p.G380R (c.1138G>A) variants in the FGFR3 gene. Both variants were not detected in her parents and therefore considered de novo. An allele-specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G>A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild-type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis). CONCLUSION: This is the second case who had two FGFR3 variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case.

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  71. Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation. Reviewed International journal

    Yuya Murase, Takuya Takeichi, Akane Kawamoto, Kana Tanahashi, Yusuke Okuno, Hiroyuki Takama, Eri Shimizu, Junko Ishikawa, Tomoo Ogi, Masashi Akiyama

    Journal of dermatological science   Vol. 97 ( 1 ) page: 50 - 56   2020.1

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    BACKGROUND: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. OBJECTIVE: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. METHODS: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. RESULTS: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32-52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46-54, CER[EOH] and CER[EOP] increased. CONCLUSION: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

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  72. Whole Exome Sequencing Contributes to Genetic Diagnosis of IBMFS Patients

    Muramatsu Hideki, Hamada Motoharu, Okuno Yusuke, Wakamatsu Manabu, Taniguchi Rieko, Narita Koutarou, Kawashima Nozomu, Kitazawa Hironobu, Ichikawa Daisuke, Nishikawa Eri, Kawashima Nazomu, Narita Atsushi, Nishio Nobuhiro, Kojima Seiji, Ogi Tomoo, Takahashi Yoshiyuki

    PEDIATRIC BLOOD & CANCER   Vol. 66   page: S63 - S64   2019.12

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  73. Whole Exome Sequencing Contributes to Genetic Diagnosis of IBMFS Patients

    Muramatsu Hideki, Hamada Motoharu, Okuno Yusuke, Wakamatsu Manabu, Taniguchi Rieko, Narita Koutarou, Kawashima Nozomu, Kitazawa Hironobu, Ichikawa Daisuke, Nishikawa Eri, Kawashima Nazomu, Narita Atsushi, Nishio Nobuhiro, Kojima Seiji, Ogi Tomoo, Takahashi Yoshiyuki

    PEDIATRIC BLOOD & CANCER   Vol. 66   page: S63-S64   2019.12

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  74. Comprehensive Mutational Analysis of Juvenile Myelomonocytic Leukemia Using Whole-Genome Sequencing

    Okuno Yusuke, Muramatsu Hideki, Murakami Norihiro, Kawashima Nozomu, Wakamatsu Manabu, Kitazawa Hironobu, Ogi Tomoo, Takahashi Yoshiyuki

    BLOOD   Vol. 134   2019.11

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    DOI: 10.1182/blood-2019-121681

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  75. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.

    Kato K, Oka Y, Muramatsu H, Vasilev FF, Otomo T, Oishi H, Kawano Y, Kidokoro H, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S

    Journal of medical genetics     2019.11

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  76. A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

    Takeichi T., Matsumoto T., Nomura T., Takeda M., Niwa H., Kono M., Shimizu H., Ogi T., Akiyama M.

    BRITISH JOURNAL OF DERMATOLOGY     2019.10

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  77. Hailey-Hailey disease with oesophageal involvement due to a previously unreported ATP2C1 mutation. Reviewed International journal

    Michihiro Kono, Masanari Kodera, Yu Inasaka, Izumi Hasegawa, Yoshinao Muro, Yuka Nakazawa, Tomoo Ogi, Masashi Akiyama

    European journal of dermatology : EJD   Vol. in press   2019.8

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  78. Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

    Thei Arjan F., Botta Elena, Raams Anja, Smith Desiree E. C., Mendes Marisa I, Caligiuri Giuseppina, Giachetti Sarah, Bione Silvia, Carriero Roberta, Liberi Giordano, Zardoni Luca, Swagemakers Sigrid M. A., Salomons Gajja S., Sarasin Alain, Lehmann Alan, van der Spek Peter J., Ogi Tomoo, Hoeijmakers Jan H. J., Vermeulen Wim, orioli Donata

    AMERICAN JOURNAL OF HUMAN GENETICS   Vol. 105 ( 2 ) page: 434-440   2019.8

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  79. Unravelling the pivotal role of DDA1 in transcription-coupled nucleotide excision repair

    Pines A., Guo C., Akita M., Theil A., Quist B., Wienholz F., Marteijn J., Demmers J., van Attikum H., Vertegaal A., Vermeulen M., Ogi T., Vermeulen W.

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 180 ( 6 ) page: E230 - E230   2019.6

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  80. Unravelling the pivotal role of DDA1 in transcription-coupled nucleotide excision repair

    Pines A, Guo C, Akita M, Theil A, Quist B, Wienholz F, Marteijn J, Demmers J, van Attikum H, Vertegaal A, Vermeulen M, Ogi T, Vermeulen W

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 180 ( 6 ) page: E230-E230   2019.6

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  81. JAK/STAT3 and NF-κB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells Reviewed

    Ken Shiraiwa, Michiko Matsuse, Yuka Nakazawa, Tomoo Ogi, Keiji Suzuki, Vladimir Saenko, Shuhang Xu, Kazuo Umezawa, Shunichi Yamashita, Kazuhiro Tsukamoto, Norisato Mitsutake

    Thyroid   Vol. 29 ( 5 ) page: 674 - 682   2019.5

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  82. A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation

    Kono Michihiro, Sawada Masaki, Nakazawa Yuka, Ogi Tomoo, Muro Yoshinao, Akiyama Masashi

    ACTA DERMATO-VENEREOLOGICA   Vol. 99 ( 4 ) page: 458-459   2019.4

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  83. Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders

    Marin Maria, Jose Ramirez Maria, Carmona Miriam Aza, Jia Nan, Ogi Tomoo, Bogliolo Massimo, Surralles Jordi

    GENES   Vol. 10 ( 1 )   2019.1

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  84. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

    Calmels Nadege, Botta Elena, Jia Nan, Fawcett Heather, Nardo Tiziana, Nakazawa Yuka, Lanzafame Manuela, Moriwaki Shinichi, Sugita Katsuo, Kubota Masaya, Obringer Cathy, Spitz Marie-Aude, Stefanini Miria, Laugel Vincent, Orioli Donata, Ogi Tomoo, Lehmann Alan Robert

    JOURNAL OF MEDICAL GENETICS   Vol. 55 ( 5 ) page: 329-343   2018.5

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  85. An adolescent case of xeroderma pigmentosum variant confirmed by the onset of sun exposure-related skin cancer during Crohn's disease treatment

    Terada Aoi, Aoshima Masahiro, Tanizaki Hideaki, Nakazawa Yuka, Ogi Tomoo, Tokura Yoshiki, Moriwaki Shinichi

    JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY   Vol. 1 ( 1 ) page: 23-26   2018.4

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    DOI: 10.1002/cia2.12011

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  86. Whole exome sequencing of 14 schizophrenia multiplex families in Japan

    Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

    HUMAN GENOMICS   Vol. 12   page: .   2018.3

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  87. Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed

    Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

    HUMAN GENOMICS   Vol. 12   2018.3

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  88. Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites

    Yasuda Takeshi, Kagawa Wataru, Ogi Tomoo, Kato Takamitsu A., Suzuki Takehiro, Dohmae Naoshi, Takizawa Kazuya, Nakazawa Yuka, Genet Matthew D., Saotome Mika, Hama Michio, Konishi Teruaki, Nakajima Nakako Izumi, Hazawa Masaharu, Tomita Masanori, Koike Manabu, Noshiro Katsuko, Tomiyama Kenichi, Obara Chizuka, Gotoh Takaya, Ui Ayako, Fujimori Akira, Nakayama Fumiaki, Hanaoka Fumio, Sugasawa Kaoru, Okayasu Ryuichi, Jeggo Penny A., Tajima Katsushi

    PLOS GENETICS   Vol. 14 ( 3 ) page: e1007277   2018.3

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    DOI: 10.1371/journal.pgen.1007277

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  89. Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.

    Doi H, Koyano S, Miyatake S, Nakajima S, Nakazawa Y, Kunii M, Tomita-Katsumoto A, Oda K, Yamaguchi Y, Fukai R, Ikeda S, Kato R, Ogata K, Kubota S, Hayashi N, Takahashi K, Tada M, Tanaka K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ogi T, Aihara M, Takeuchi H, Matsumoto N, Tanaka F

    Journal of human genetics     2018.2

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    DOI: 10.1038/s10038-017-0408-5

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  90. Disorders with deficiency in TC-NER: Molecular pathogenesis of cockayne syndrome and UV-Sensitive syndrome

    Guo C.

    DNA Repair Disorders     page: 25-40   2018.1

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    DOI: 10.1007/978-981-10-6722-8_2

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  91. Erratum: Author Correction: Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair (Nature communications (2017) 8 (16102)) Reviewed International journal

    Niida H, Matsunuma R, Horiguchi R, Uchida C, Nakazawa Y, Motegi A, Nishimoto K, Sakai S, Ohhata T, Kitagawa K, Moriwaki S, Nishitani H, Ui A, Ogi T, Kitagawa M

    Nature communications   Vol. 9   page: 16214 - 16214   2018

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    This corrects the article DOI: 10.1038/ncomms16102.

    DOI: 10.1038/ncomms16214

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    Other Link: http://orcid.org/0000-0002-5492-9072

  92. Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways

    Okuda Masahiko, Nakazawa Yuka, Guo Chaowan, Ogi Tomoo, Nishimura Yoshifumi

    NUCLEIC ACIDS RESEARCH   Vol. 45 ( 22 ) page: 13043-13055   2017.12

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    DOI: 10.1093/nar/gkx970

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  93. ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair

    Tsuda Masataka, Cho Kosai, Ooka Masato, Shimizu Naoto, Watanabe Reiko, Yasui Akira, Nakazawa Yuka, Ogi Tomoo, Harada Hiroshi, Agama Keli, Nakamura Jun, Asada Ryuta, Fujiike Haruna, Sakuma Tetsushi, Yamamoto Takashi, Murai Junko, Hiraoka Masahiro, Koike Kaoru, Pommier Yves, Takeda Shunichi, Hirota Kouji

    PLOS ONE   Vol. 12 ( 11 ) page: e0188320   2017.11

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    DOI: 10.1371/journal.pone.0188320

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  94. Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells

    Doi Ryoichiro, Tsuchiya Tomoshi, Mitsutake Norisato, Nishimura Satoshi, Matsuu-Matsuyama Mutsumi, Nakazawa Yuka, Ogi Tomoo, Akita Sadanori, Yukawa Hiroshi, Baba Yoshinobu, Yamasaki Naoya, Matsumoto Keitaro, Miyazaki Takuro, Kamohara Ryotaro, Hatachi Go, Sengyoku Hideyori, Watanabe Hironosuke, Obata Tomohiro, Niklason Laura E., Nagayasu Takeshi

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 8447   2017.8

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    DOI: 10.1038/s41598-017-09115-2

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  95. Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair

    Niida Hiroyuki, Matsunuma Ryoichi, Horiguchi Ryo, Uchida Chiharu, Nakazawa Yuka, Motegi Akira, Nishimoto Koji, Sakai Satoshi, Ohhata Tatsuya, Kitagawa Kyoko, Moriwaki Shinichi, Nishitani Hideo, Ui Ayako, Ogi Tomoo, Kitagawa Masatoshi

    NATURE COMMUNICATIONS   Vol. 8   page: 16102   2017.7

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    DOI: 10.1038/ncomms16102

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  96. An XPA gene splicing mutation resulting in trace protein expression in an elderly patient with xeroderma pigmentosum group A without neurological abnormalities

    Takahashi Y., Endo Y., Kusaka-Kikushima A., Nakamaura S., Nakazawa Y., Ogi T., Uryu M., Tsuji G., Furue M., Moriwaki S.

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 177 ( 1 ) page: 253-257   2017.7

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    DOI: 10.1111/bjd.15051

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  97. Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules

    Okubo Yumi, Masuyama Ritsuko, Iwanaga Akira, Koike Yuta, Kuwatsuka Yutaka, Ogi Tomoo, Yamamoto Yosuke, Endo Yuichiro, Tamura Hiroshi, Utani Atsushi

    PLOS ONE   Vol. 12 ( 5 ) page: e0177375   2017.5

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    DOI: 10.1371/journal.pone.0177375

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  98. PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast

    Daigaku Yasukazu, Etheridge Thomas J., Nakazawa Yuka, Nakayama Mayumi, Watson Adam T., Miyabe Izumi, Ogi Tomoo, Osborne Mark A., Carr Antony M.

    PLOS GENETICS   Vol. 13 ( 5 ) page: e1006789   2017.5

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    DOI: 10.1371/journal.pgen.1006789

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  99. Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum. Reviewed

    Iwanaga A, Okubo Y, Yozaki M, Koike Y, Kuwatsuka Y, Tomimura S, Yamamoto Y, Tamura H, Ikeda S, Maemura K, Tsuiki E, Kitaoka T, Endo Y, Mishima H, Yoshiura KI, Ogi T, Tanizaki H, Wataya-Kaneda M, Hattori T, Utani A

    The Journal of dermatology     2017.2

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    DOI: 10.1111/1346-8138.13727

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  100. A 10-year follow-up of a child with mild case of xeroderma pigmentosum complementation group D diagnosed by whole-genome sequencing. Reviewed

    Ono R, Masaki T, Mayca Pozo F, Nakazawa Y, Swagemakers SM, Nakano E, Sakai W, Takeuchi S, Kanda F, Ogi T, van der Spek PJ, Sugasawa K, Nishigori C

    Photodermatology, photoimmunology & photomedicine   Vol. 32 ( 4 ) page: 174-80   2016.7

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    DOI: 10.1111/phpp.12240

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  101. Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency.

    Tamura S, Higuchi K, Tamaki M, Inoue C, Awazawa R, Mitsuki N, Nakazawa Y, Mishima H, Takahashi K, Kondo O, Imai K, Morio T, Ohara O, Ogi T, Furukawa F, Inoue M, Yoshiura K, Kanazawa N

    Clinical immunology (Orlando, Fla.)   Vol. 160 ( 2 ) page: 255-60   2015.10

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    DOI: 10.1016/j.clim.2015.07.004

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  102. XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency.

    The Journal of allergy and clinical immunology   Vol. 136 ( 4 ) page: 1007-17   2015.10

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    DOI: 10.1016/j.jaci.2015.06.007

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  103. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.

    Alagoz M, Katsuki Y, Ogiwara H, Ogi T, Shibata A, Kakarougkas A, Jeggo P

    Nucleic acids research   Vol. 43 ( 16 ) page: 7931-44   2015.9

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    DOI: 10.1093/nar/gkv722

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  104. Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    Guo CY, Luo L, Urata Y, Goto S, Huang WJ, Takamura S, Hayashi F, Doi H, Kitajima Y, Ono Y, Ogi T, Li TS

    Scientific reports   Vol. 5   page: 8055   2015.1

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    DOI: 10.1038/srep08055

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  105. A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents.

    Jia N, Nakazawa Y, Guo C, Shimada M, Sethi M, Takahashi Y, Ueda H, Nagayama Y, Ogi T

    Nature protocols   Vol. 10 ( 1 ) page: 12-24   2015.1

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    DOI: 10.1038/nprot.2014.194

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  106. Hypomorphic PCNA mutation underlies a human DNA repair disorder.

    Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, Crosby AH

    The Journal of clinical investigation   Vol. 124 ( 7 ) page: 3137-46   2014.7

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    DOI: 10.1172/JCI74593

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  107. PRKDC mutations in a SCID patient with profound neurological abnormalities.

    Woodbine L, Neal JA, Sasi NK, Shimada M, Deem K, Coleman H, Dobyns WB, Ogi T, Meek K, Davies EG, Jeggo PA

    The Journal of clinical investigation   Vol. 123 ( 7 ) page: 2969-80   2013.7

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    DOI: 10.1172/JCI67349

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  108. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

    Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H, Wing JF, Lewin SO, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Yamashita S, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Takahashi Y, Nagayama Y, Mitsutake N, Lehmann AR, Ogi T

    American journal of human genetics   Vol. 92 ( 5 ) page: 807-19   2013.5

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    DOI: 10.1016/j.ajhg.2013.04.007

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  109. [Molecular cloning and characterisation of UVSSA, the responsible gene for UV-sensitive syndrome].

    Ogi T, Nakazawa Y, Sasaki K, Guo C, Yoshiura K, Utani A, Nagayama Y

    Seikagaku. The Journal of Japanese Biochemical Society   Vol. 85 ( 3 ) page: 133-44   2013.3

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  110. Functional characterization of the novel BRAF complex mutation, BRAF(V600delinsYM) , identified in papillary thyroid carcinoma.

    Matsuse M, Mitsutake N, Tanimura S, Ogi T, Nishihara E, Hirokawa M, Fuziwara CS, Saenko VA, Suzuki K, Miyauchi A, Yamashita S

    International journal of cancer. Journal international du cancer   Vol. 132 ( 3 ) page: 738-43   2013.2

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    DOI: 10.1002/ijc.27709

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  111. miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts.

    Kashiyama K, Mitsutake N, Matsuse M, Ogi T, Saenko VA, Ujifuku K, Utani A, Hirano A, Yamashita S

    The Journal of investigative dermatology   Vol. 132 ( 6 ) page: 1597-604   2012.6

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    DOI: 10.1038/jid.2012.22

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  112. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.

    Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, Takahashi Y, Ohyama K, Ito K, Mishima H, Nomura M, Kinoshita A, Ono S, Takenaka K, Masuyama R, Kudo T, Slor H, Utani A, Tateishi S, Yamashita S, Stefanini M, Lehmann AR, Yoshiura K, Ogi T

    Nature genetics   Vol. 44 ( 5 ) page: 586-92   2012.5

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    DOI: 10.1038/ng.2229

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  113. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome.

    Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, Prescott K, Suri M, Byrd PJ, Matsuse M, Mitsutake N, Nakazawa Y, Vasudevan P, Barrow M, Stewart GS, Taylor AM, O'Driscoll M, Jeggo PA

    PLoS genetics   Vol. 8 ( 11 ) page: e1002945   2012

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    DOI: 10.1371/journal.pgen.1002945

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  114. Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly.

    Matsumoto Y, Miyamoto T, Sakamoto H, Izumi H, Nakazawa Y, Ogi T, Tahara H, Oku S, Hiramoto A, Shiiki T, Fujisawa Y, Ohashi H, Sakemi Y, Matsuura S

    DNA repair   Vol. 10 ( 3 ) page: 314-21   2011.3

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    DOI: 10.1016/j.dnarep.2010.12.002

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  115. A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives.

    Nakazawa Y, Yamashita S, Lehmann AR, Ogi T

    DNA repair   Vol. 9 ( 5 ) page: 506-16   2010.5

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    DOI: 10.1016/j.dnarep.2010.01.015

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  116. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells.

    Ogi T, Limsirichaikul S, Overmeer RM, Volker M, Takenaka K, Cloney R, Nakazawa Y, Niimi A, Miki Y, Jaspers NG, Mullenders LH, Yamashita S, Fousteri MI, Lehmann AR

    Molecular cell   Vol. 37 ( 5 ) page: 714-27   2010.3

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    DOI: 10.1016/j.molcel.2010.02.009

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  117. Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair.

    Nakamura K, Kogame T, Oshiumi H, Shinohara A, Sumitomo Y, Agama K, Pommier Y, Tsutsui KM, Tsutsui K, Hartsuiker E, Ogi T, Takeda S, Taniguchi Y

    PLoS genetics   Vol. 6 ( 1 ) page: e1000828   2010.1

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    DOI: 10.1371/journal.pgen.1000828

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  118. A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU).

    Limsirichaikul S, Niimi A, Fawcett H, Lehmann A, Yamashita S, Ogi T

    Nucleic acids research   Vol. 37 ( 4 ) page: e31   2009.3

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    DOI: 10.1093/nar/gkp023

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  119. Translesion synthesis: Y-family polymerases and the polymerase switch.

    Lehmann AR, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing JF, Kannouche PL, Green CM

    DNA repair   Vol. 6 ( 7 ) page: 891-9   2007.7

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    DOI: 10.1016/j.dnarep.2007.02.003

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  120. Differential Bvg phase-dependent regulation and combinatorial role in pathogenesis of two Bordetella paralogs, BipA and BcfA.

    Sukumar N, Mishra M, Sloan GP, Ogi T, Deora R

    Journal of bacteriology   Vol. 189 ( 10 ) page: 3695-704   2007.5

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    DOI: 10.1128/JB.00009-07

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  121. The Y-family DNA polymerase kappa (pol kappa) functions in mammalian nucleotide-excision repair.

    Ogi T, Lehmann AR

    Nature cell biology   Vol. 8 ( 6 ) page: 640-2   2006.6

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    DOI: 10.1038/ncb1417

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  122. Involvement of vertebrate Polkappa in translesion DNA synthesis across DNA monoalkylation damage.

    Takenaka K, Ogi T, Okada T, Sonoda E, Guo C, Friedberg EC, Takeda S

    The Journal of biological chemistry   Vol. 281 ( 4 ) page: 2000-4   2006.1

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    DOI: 10.1074/jbc.M506153200

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  123. Binding and transcriptional activation of non-flagellar genes by the Escherichia coli flagellar master regulator FlhD2C2.

    Stafford GP, Ogi T, Hughes C

    Microbiology (Reading, England)   Vol. 151 ( Pt 6 ) page: 1779-88   2005.6

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    DOI: 10.1099/mic.0.27879-0

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  124. Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis.

    Bavoux C, Leopoldino AM, Bergoglio V, O-Wang J, Ogi T, Bieth A, Judde JG, Pena SD, Poupon MF, Helleday T, Tagawa M, Machado C, Hoffmann JS, Cazaux C

    Cancer research   Vol. 65 ( 1 ) page: 325-30   2005.1

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  125. Localisation of human Y-family DNA polymerase kappa: relationship to PCNA foci.

    Ogi T, Kannouche P, Lehmann AR

    Journal of cell science   Vol. 118 ( Pt 1 ) page: 129-36   2005.1

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    DOI: 10.1242/jcs.01603

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  126. Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53.

    Wang Y, Seimiya M, Kawamura K, Yu L, Ogi T, Takenaga K, Shishikura T, Nakagawara A, Sakiyama S, Tagawa M, O-Wang J

    International journal of oncology   Vol. 25 ( 1 ) page: 161-5   2004.7

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  127. Mammalian Pol kappa: regulation of its expression and lesion substrates.

    Ohmori H, Ohashi E, Ogi T

    Advances in protein chemistry   Vol. 69   page: 265-78   2004

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    DOI: 10.1016/S0065-3233(04)69009-7

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  128. The absence of DNA polymerase kappa does not affect somatic hypermutation of the mouse immunoglobulin heavy chain gene.

    Shimizu T, Shinkai Y, Ogi T, Ohmori H, Azuma T

    Immunology letters   Vol. 86 ( 3 ) page: 265-70   2003.5

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  129. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis.

    Schuster M, Lostroh CP, Ogi T, Greenberg EP

    Journal of bacteriology   Vol. 185 ( 7 ) page: 2066-79   2003.4

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  130. Polkappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene.

    Ogi T, Shinkai Y, Tanaka K, Ohmori H

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 99 ( 24 ) page: 15548-53   2002.11

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    DOI: 10.1073/pnas.222377899

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  131. [Biochemical studies of human DNA polymerase kappa and its transcriptional regulation].

    Ohashi E, Ogi T, Ohmori H

    Seikagaku. The Journal of Japanese Biochemical Society   Vol. 74 ( 3 ) page: 218-23   2002.3

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  132. Expression of human and mouse genes encoding polkappa: testis-specific developmental regulation and AhR-dependent inducible transcription.

    Ogi T, Mimura J, Hikida M, Fujimoto H, Fujii-Kuriyama Y, Ohmori H

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 6 ( 11 ) page: 943-53   2001.11

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  133. [Mutagenesis by Escherichia coli DinB and its mammalian homolog Pol kappa].

    Ogi T, Ohashi E, Ohmori H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   Vol. 46 ( 8 Suppl ) page: 1155-61   2001.6

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  134. Error-prone bypass of certain DNA lesions by the human DNA polymerase kappa.

    Ohashi E, Ogi T, Kusumoto R, Iwai S, Masutani C, Hanaoka F, Ohmori H

    Genes & development   Vol. 14 ( 13 ) page: 1589-94   2000.7

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  135. Identification of additional genes belonging to the LexA regulon in Escherichia coli.

    Molecular microbiology   Vol. 35 ( 6 ) page: 1560-72   2000.3

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  136. Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein dinB.

    Ogi T, Kato T Jr, Kato T, Ohmori H

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 4 ( 11 ) page: 607-18   1999.11

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Books 1

  1. Disorders with deficiency in TC-NER: Molecular pathogenesis of cockayne syndrome and UV-Sensitive syndrome

    Guo C., Ogi T.( Role: Sole author)

    DNA Repair Disorders  2018.1  ( ISBN:9789811067211

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    Nucleotide excision repair (NER) is one of the most important DNA repair systems involved in removing a wide range of DNA damage from the genome. NER consists of two sub-pathways: the global genome nucleotide excision repair (GG-NER) pathway, which removes DNA lesions generated in the whole genome (as described in Chap. 1 of this book), and the transcription-coupled nucleotide excision repair (TC-NER) pathway, which removes lesions specifically from the transcribed strands of actively transcribed genes. At least 20 factors are involved in the TC-NER process, and mutations in the genes responsible for coding these factors may mainly result in two human genetic disorders: Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS). Despite similar molecular defects in TC-NER, CS and UVSS show distinct clinical phenotypes. CS patients display severe developmental and neurological abnormalities as well as premature ageing, whereas UVSS individuals only show milder cutaneous abnormalities, such as hypersensitivity to UV light. The molecular basis for the difference in the clinical features remains unclear. In this chapter, we will specifically describe the historical progress and recent findings of TC-NER and summarize the current understanding of the molecular pathogenesis of CS and UVSS.

    DOI: 10.1007/978-981-10-6722-8_2

    Scopus

Presentations 2

  1. RNA polymerase IIのユビキチン化修飾による転写共役修復開始反応の分子機構とその破綻により発症する哺乳類の神経変性のメカニズム

    荻朋男

    第42回日本分子生物学会年会  2019.12.5 

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  2. 希少未診断疾患におけるゲノム解析およびデータ評価パイプラインの構築

    中沢由華, 原雄一郎, 遠山美穂, 岡泰由, 荻朋男

    第4回名大医薬系3部局交流シンポジウム  2019.10.31 

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Works 17

  1. 紫外線感受性症候群責任因子によるRNAポリメラーゼユビキチン化と待避機構の解析

    2012
    -
    2014

  2. ヌクレオチド除去修復欠損性日光過敏症のウイルス発現系とゲノム解析による網羅的探索

    2012
    -
    2014

  3. 放射線損傷DNA修復過程における複製忠実度の 低いDNAポリメラーゼによる突然変異誘発機構の解析

    2011
    -
    2012

  4. ヌクレオチド除去修復過程における修復DNA合成の分子メカニズムの解明

    2010
    -
    2011

  5. 紫外線DNA損傷修復研究

    2010
    -
    2011

  6. 紫外線DNA損傷修復研究

    2010
    -
    2011

  7. DNA損傷の修復合成過程におけるDNAポリメラーゼの選択機構と、複製エラーを伴うDNA修復による突然変異誘発機構の解明

    2010
    -
    2011

  8. DNA修復過程でのヌクレオシドの取り込みを指標とした不正確な修復合成を誘発するDNA修復因子の探索

    2010
    -
    2011

  9. 放射線DNA損傷の新たな修復メカニズムの解明と放射線誘発がん予防のためのリスク評価

    2009
    -
    2011

  10. DNA損傷修復過程における複製忠実度の低いDNAポリメラーゼの機能解析

    2009
    -
    2010

  11. 化粧品添加物および日光過敏症新薬開発を目的とする光DNA損傷修復遺伝子のスクリーニング

    2009
    -
    2010

  12. 紫外線防護効果の高い化粧品添加物の高速スクリーニング技術の開発

    2009
    -
    2010

  13. 養蜂製品の光DNA損傷修復促進効果に関する基礎的研究と 高機能化粧品添加物としての有用性評価

    2009
    -
    2010

  14. DNA損傷修復過程において複製精度の低いDNAポリメラーゼが選択される仕組みと、DNA修復に起因する突然変異の蓄積に伴う発がんメカニズムの解明

    2009
    -
    2010

  15. DNA修復過程における複製忠実度の低いDNAポリメラーゼの機能解析

    2009
    -
    2010

  16. 放射線損傷DNA修復過程における複製忠実度の 低いDNAポリメラーゼによる突然変異誘発機構の解析

    2009
    -
    2010

  17. 修復DNA合成過程でのポリメラーゼ選択機構と複製忠実度の低いDNAポリメラーゼの作用による突然変異誘発メカニズムの解明

    2009
    -
    2010

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Research Project for Joint Research, Competitive Funding, etc. 7

  1. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  2. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  3. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  4. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  5. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費助成事業 

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    Grant type:Competitive

  6. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費助成事業 

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    Grant type:Competitive

  7. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費助成事業 

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    Grant type:Competitive

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KAKENHI (Grants-in-Aid for Scientific Research) 33

  1. 甲状腺癌オルガノイドを用いた放射性ヨウ素治療抵抗性機序の解明

    Grant number:23H02860  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(B)

    光武 範吏, 工藤 崇, 星野 大輔, 菅沼 伸康, 荻 朋男

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    Authorship:Coinvestigator(s) 

    放射性ヨウ素(RAI)内用療法は、若年者では著効例が見られる一方、高齢者ではしばしばRAI治療抵抗性(RAI-R)であり、RAI-Rは年齢が強い相関因子である。それに加え、研究担当者らはTERT遺伝子プロモーターの変異もRAI-Rに関連することを明らかにした。
    本研究では、担当者らが独自に確立したオルガノイドライブラリーを用い、TERTプロモーター変異を始めとする遺伝子異常が、どのような仕組みでRAI-Rを誘導するのか、その分子機序の解明を行い、RAI-R克服の基盤とする。

  2. 人はなぜ老い・病(やまい)になるのか-環境ストレス病態相関の理解

    Grant number:23H00516  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(A)

    荻 朋男, 光武 範吏, 真下 知士

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    Authorship:Principal investigator 

    Grant amount:\47450000 ( Direct Cost: \36500000 、 Indirect Cost:\10950000 )

    本研究では、マルチオミクス解析技術を用いた横断的アプローチにより、老化やがんなどの疾患発症に関連する、環境ストレス因子を特定し、主要な環境因子と影響を受ける臓器や疾患との関係 「環境ストレス病態相関」を明らかにする。併せて、環境ストレスから生体を防御する 「環境ストレス応答・ゲノム修復機構」の作動原理を理解し、その破綻により発症する疾患の病態解明を目指す。

  3. 細胞種によって放射線被ばく刻印は異なるのか?

    Grant number:22K19674  2022.6 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    光武 範吏, 荻 朋男

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    人体への放射線被ばくの晩発影響として最も重要なのは発癌であるが、癌は最もよく見られる疾患の一つであり、被ばくした「集団」の癌発症数の増加は観察可能でも、「あるひとつの癌」が放射線で引き起こされたものか、その他の原因で起きたものかを区別する方法は今のところない。本研究では、細胞腫によるクロマチン状態の違いに着目し、放射線による欠失を上手く修復できる部位があるという仮説を検証することによって、放射線リスク研究に、集団ではなく個々の癌における放射線影響の有無を調べる手段を提供する。

  4. 薬剤耐性・変異株解析可能なリアルタイム次世代シークエンスによる重症感染症迅速診断

    Grant number:22K07818  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    伊藤 嘉規, 荻 朋男

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    Authorship:Coinvestigator(s) 

    ロングリード法に使用するナノポアシークエンサーは、遺伝子配列の解析に同時平行して解析情報を見ることが可能なため、短時間で微生物を同定可能であり「リアルタイムシークエンス法」と表現できる。リアルタイムシークエンス法では、6時間程度で、薬剤耐性情報を含む網羅的な微生物診断が可能となる。ナノポアシークエンサーは、技術改良が進んでおり、本研究では、重症感染症の網羅的・迅速診断法としてのリアルタイムシークエンス法の基盤的検証を行う。

  5. 転写共役修復 (TCR)の分子メカニズム解明とTCR欠損ヒト遺伝性疾患の分子病態

    Grant number:21H02399  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(B)

    中沢 由華, 荻 朋男

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    転写と共役したDNA修復機構 (transcription coupled repair: TCR)は、転写が活発に行われている領域に生じたDNA損傷を効率良く修復するシステムであり、生体の恒常性維持に重要なメカニズムである。本研究では、DNA損傷箇所で停止したRNA合成酵素がユビキチン化修飾を受けてTCRを開始・制御する分子機構の詳細解明に取り組むとともに、TCRの破綻により発症するヒト疾患の病態を明らかにすることを目指す。

  6. ロングリード配列決定法による放射線被ばく刻印の同定

    Grant number:20K21718  2020.7 - 2023.3

    科学研究費助成事業  挑戦的研究(萌芽)

    光武 範吏, 鈴木 啓司, 荻 朋男

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    放射線被ばくによって癌が発生するのは明らかであるが、あるひとつの癌が放射線で引き起こされたものか、その他の原因で起きたものかを区別する方法は今のところない。放射線はクラスター損傷と呼ばれる複雑な異常をDNAに引き起こし、マイクロホモロジーを伴う欠失や逆位を生じさせるとされるが、これらを全ゲノムレベルで解析する手法は今までなかった。本研究では、様々な線量の放射線を照射し樹立したHPRT変異細胞クローンと、新規技術であるロングリードシークエンシングを用い、上記の欠失や逆位を全ゲノムレベルで解析し、放射線刻印とも呼べる放射線特異的なゲノム変化の有無を明らかにする。
    本研究の目的は、最新のゲノム解析技術、特にロングリード次世代ゲノム解析を用い、放射線ゲノム刻印の存在を明らかにし、放射線リスク研究に、集団ではなく個々の癌における放射線影響の有無を調べる手段を提供することである。そのため、長年様々な研究で使用されている放射線照射HPRT変異クローンを用いた。
    前年度に確立した上記クローンについて、無処理、ガンマ線照射(1, 3, 6 Gy)クローンをそれぞれ5クローン、N-ethyl-N-nitrosourea(ENU, 1 mM, 1 hr)処理クローンを4クローンを対象に、Oxford Nanopore Technologies社のロングリードシークエンサーによるゲノム解析を行った。
    R3年度は、放射線で引き起こされやすいとされる欠失について解析を行った。シークエンサーから得られたリードデータをminimap2を用いてヒトゲノムレファレンス配列GRCh38にマッピングし、snifflesを用いて構造変異のコールを行った。十数キロベースの欠失までは、リード内に直接的に観察することができた。各クローンのvcfファイルはSURVIVORを用いてまとめ、全クローンにおいて見られる変異を除外し、変異アレル頻度と変異をサポートするリード数が一定以上の変異を抽出してクローン間の比較解析を行った。放射線照射クローンでユニークに見られた変異は、メガベース以上の大きな欠失が線量依存的に増加していた。これは前年度に行ったPCRベースの解析とも一致していた。ただ、無処理クローン間でも相当程度の変異の違いがあり、ウシ胎児血清添加下の通常の培養環境では、それなりに変異が入ることが示唆された。
    全ゲノム解析に関しては順調に施行することができたが、通常の培養環境でも相当数の変異が入り、放射線に特徴的な配列等の付加情報の探索を行う必要性が考えられた。
    全ゲノム解析を継続し、多角的な面より詳細な解析を行っていく。

  7. MYRF遺伝子を起点とした発熱時言動異常の病態解明

    Grant number:20K08241  2020.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    倉橋 宏和, 岡田 洋平, 奥村 彰久, 荻 朋男

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    我が国において、発熱に伴ってうわごとを言うなどの意識障害は稀ではなく、重篤な場合はインフルエンザ感染に伴う異常言動のように社会問題となりえます。MERS(可逆性脳梁膨大部病変を有する軽症脳炎・脳症)は、発熱に伴い異常言動を呈する代表的な急性脳症です。我々は、2家系のMERS家族例においてMYRF遺伝子変異を同定しました。この研究は、MYRF遺伝子に着目して、その遺伝学的背景をより明らかにすること、また、変異MYRFについてモデル動物やモデル細胞を作成し、その特徴を明らかにすることを目的としています。
    MERS(可逆性脳梁膨大部病変を有する軽症脳炎・脳症)は、発熱に伴い異常言動を呈する急性脳症である。急性期の頭部MRIで脳梁膨大部に異常信号を呈することが特徴で、大脳白質の主要な構成要素であるミエリンの障害が示唆されている。我々は、2家系のMERS-異常言動スペクトラム家族例においてMYRF遺伝子変異を同定し、発熱時の異常言動と深く関わっている可能性を見出した。MYRFはオリゴデンデンドロサイトに発現し、ミエリン化・髄鞘維持に必要なDNA転写調節因子である。本研究の目的は、MYRF遺伝子に着目してMERS-異常言動スペクトラムの病態を解明することである。この目的を達成するために以下の研究を行なっている。1)MERS-異常言動スペクトラム症例に対する次世代シークエンス解析: MYRFにより発現が制御される遺伝子のうちミエリンに発現するものは約700あると報告されている。我々はMERS反復例・家族例を収集し、MYRF遺伝子に加えて、これらのMYRF遺伝子により発現が制御されうる遺伝子に注目してバリアントの解析を行っている。また、MERS症例だけでなく、発熱に伴う言動異常を呈した症例についても、同様の解析を行う。2)iPS細胞用いた研究:MYRF遺伝子変異を伴うMERS患者由来のiPS細胞作成、および、iPS細胞からオリゴデンドロサイトへの分化をより効率的に行うための実験を行なっている。今後も条件を変えて分化誘導の効率向上を試みる。また同時に、患者検体からのiPS細胞樹立を進める。
    MERS-異常言動スペクトラム症例に対する次世代シークエンス解析:MYRF遺伝子変異を認めた家系以外の症例を集積し、MERS反復例・家族例に対し次世代シークエンス解析を行った。MYRFが発現に関与している可能性のある遺伝子のバリアントに着目して解析を行った。その結果、遺伝子全体でのバリアントの数は対照群と差がなく、高頻度でバリアントを認める遺伝子も同定できなかったものの、低頻度ながらバリアントを認める遺伝子は対照群とは異なっていた。バリアントを認める遺伝子のうち、中枢神経系と関連の強いものに着目して解析を進める。
    iPS細胞を用いた研究:オリゴデンドロサイトへの分化を短時間で効率的に行うために、我々は酸素条件に着目し、至適な酸素濃度について検討を行っている。また、MYRF遺伝子変異を伴うMERS患者由来のiPS細胞を作成中である。
    次世代シークエンス解析については、今後も新規症例を集積し解析を継続する。低酸素状態など、さまざまな条件での分化効率の検討を継続している。その結果をもとに、患者由来のiPS細胞からも分化誘導を試みる。

  8. Molecular pathogenesis of human disorders associated with deficiencies in the DNA repair and environmental stress response systems

    Grant number:20H00629  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

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    Authorship:Principal investigator 

    Grant amount:\45370000 ( Direct Cost: \34900000 、 Indirect Cost:\10470000 )

  9. 次世代シークエンスによる包括的な重症感染症リキッドバイオプシー

    Grant number:19K08298  2019.4 - 2023.3

    科学研究費助成事業  基盤研究(C)

    伊藤 嘉規, 川田 潤一, 荻 朋男

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    近年の分子生物学の進展を応用し、侵襲性の少ない、包括的(微生物と生体情報をともに含む)な重症診断法開発の基盤となる研究を行う。病原微生物である、細菌、ウイルス、真菌などは、培養や核酸検出など様々な方法で検出されるが、次世代シークエンスは網羅的な微生物検出が可能である。他方、血液などの体液中には、細胞から分泌されるエクソソーム、Cell-free DNA、マイクロRNAが存在する。これらの微小な細胞由来分子を分離・解析し、重症感染症患者の炎症反応、免疫応答や臓器障害に関する評価を行い、リキッドバイオプシー(体液による病態解析・診断)を可能とするアッセイシステムを構築する。
    重症感染症では、早期診断と適切な抗微生物薬の選択が予後を左右する。次世代シークエンス法は、一度のアッセイで、1,000万~10億程度のリード(DNA・RNA断片のシークエンス数)を得ることができ、臨床検体中の核酸断片を網羅的・定量的に解析できる。さらに薬剤耐性も同時に解析可能である。重症感染症における病原微生物診断は現状では不十分であり、多くの症例で診断できれば、抗微生物薬の効率的な使用が可能になり、感染症診療に大きな進展が予想される。生体内の微生物分布(マイクロバイオーム)を調べる方法は臨床診断法にそのまま応用できない。次世代シークエンス法を臨床応用できる基盤的研究を推進し、重症感染症の病原を早期に網羅的に診断できる方法を開発する。
    2021年度は、150bpの断片配列を読むショートリード法、網羅的な解析であるショットガン法の組み合わせにより、血液培養・核酸検出法に比べて、病原微生物検出における次世代シークエンスの優位性を引き続き検討した。シークエンスデータの解析は、2019年に独自に開発した解析パイプライン「PATHDET」をアップデートし、使用した。小児中枢神経感染症では、病原微生物が同定されない症例を多く経験する。そこで、中枢神経感染症を疑われた1歳未満の小児28例を後方視的に検討した。2名の患児では、病原微生物は診断されていた(Proteus mirabilisが1例、Human parvovirus B19が1例)。抽出したDNAおよびRNAの解析を行った結果、前述の2例では同一の微生物が検出され、さらに、Coxsackievirus B5が4例、Coxsackievirus B4が3例、Echovirus E7が1例、Human parechovirus 3が1例に検出された。全体で、原因不明であった患者26例中10例(38%)の病原微生物を明らかにした。
    2021年度は、前年度に引き続き、病原微生物が同定しにくい重症疾患である小児中枢神経感染症の髄液検体を解析した結果を報告し、次世代シークエンス法の病原微生物診断における有用性が示された。重症感染症の血液中リンパ球の次世代シークエンス・シングルセル解析を、EBウイルス関連血球貪食性リンパ組織球症で開始していたが、ウイルス感染細胞の性状や免疫反応、炎症反応の性質について、症例を増やしながら継続して解析を行った。
    次世代シークエンスを用いた病原微生物診断に関しては、ショットガン・メタゲノム法と比較しながら、ロングリードシークエンス法の有用性の検討を進める。重症感染症の血液・髄液検体のcell-free DNAおよびmiRNAの分離・解析に関しては、先天性サイトメガロウイルス感染症の中枢神経障害に関するmiRNAの解析を予定している。

  10. Development of new technology to evaluate the transcription-coupling repair factors.

    Grant number:19H04266  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Hashimoto Satoru

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    Exposure to various environmental factors give rise DNA damage, which is repaired by multiple mechanisms. The encounter of DNA damage by RNA polymerase in the transcription region initiate DNA repair, but the detailed mechanism remains unclear because of the lack of experimental system for evaluating the site-specific phenomenon on the genome where RNA polymerases encounter against DNA damage. In this research project, we aim to develop a new experimental system for evaluating RNA polymerase that encounter against DNA damage in order to elucidate the damage recognition mechanism by RNA polymerase.

  11. Interactome analysis after induction of DNA damage in human cells

    Grant number:18K11639  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kurotani Kenichi

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    DNA damage response (DDR) is a crucial response for genome stability. A detailed understanding of their protein-protein interaction networks enables us to know the cellular function of DDR proteins. In this project, we performed the interactome analysis of DDR proteins in human cells using a high resolution mass spectrometry. In the results of our study, we identified several factors that interact with POLR2A/RPB1, the largest subunit of RNA polymerase II, after induction of DNA damage in human cells.

  12. Elucidation of the molecular pathogenesis of genetic disorders caused by defects in DNA damage response using deep proteomic analysis

    Grant number:18H03372  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Oka Yasuyoshi

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    DNA damage response is prerequisite for the maintenance of genomic stability. Mutations in genes encoding many components of DNA damage response can result in a number of genetic disorders. Recent extensive studies using NGS analysis identify pathogenic mutations in patients with genomic instability. Because the average healthy person has dozens of genetic variants predicted to severely disrupt protein-coding genes, known as loss-of-function variants, and WES is not able to detect chromosomal translocations, large chromosomal deletions and non-canonical splicing mutations, it is difficult to narrow down and identify pathogenic mutations from patients with extremely rare genetic diseases using only NGS technologies. Using deep proteome analysis, we found the novel disease-causing mutation in the RNASEH2B gene from the patient with microcephaly, cerebral atrophy, and basal ganglia calcification, who was undiagnosed using a WES analysis.

  13. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    科学研究費補助金  その他

  14. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費補助金  基盤研究(A)

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    Authorship:Principal investigator 

  15. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    科学研究費補助金  その他

  16. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費補助金  その他

  17. Molecular pathogenesis of human genetic disorders associated with deficiency in the DNA repair and damage response system

    Grant number:17H00783  2017.4 - 2020.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\42770000 ( Direct Cost: \32900000 、 Indirect Cost:\9870000 )

    We have investigated on human genetic disorders associated with genome instability. Patients with these syndromes have developed various clinical manifestations due to malfunctions of DNA repair and damage response system. We have collected undiagnosed cases and tried to elucidate the genetic cause of diseases using the Multi-omics approach that involves next-generation sequencing, high-accurate mass spectrometry, and precise DNA repair assays. Once we identified pathogenic variants, we have performed in vitro and in vivo analyses as well as animal studies so that we could get new insights into the molecular pathogenesis of the diseases. Recently, we have reported a detailed molecular mechanism of the initiation of transcription-coupled repair, which is compromised in Cockayne syndrome.

  18. DNA double strand break repair factors mutated in a new syndrome with microcephaly

    Grant number:17H01877  2017.4 - 2020.3

    NAKAZAWA Yuka

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    In this study, we have focused on microcephaly as a commonly observed clinical feature of DNA repair deficiency disorders. We have identified several new pathogenic variants in DNA repair genes from microcephaly cases and tried to elucidate their molecular pathogenesis. We have generated mice with mutations in those newly determined genes; however, we often experienced lack of expected phenotypes. This is partly due to greater tolerance to DNA damages in mice; we decided to cross the animals with other mice with deficiency in different DNA repair processes so that overload DNA damage to elicit a phenotype. From this approach, we found that microcephaly and some types of neurodegeneration diseases can be explained by prolonged arrest of RNA polymerases at DNA damage sites during transcription. DNA damage stalled RNA polymerases are ubiquitinated to facilitate DNA repair; when this process is compromised, various neurodegenerative phenotypes, as shown in Cockayne syndrome, come up.

  19. Genetic diagnosis of microcephaly

    Grant number:16K15526  2016.4 - 2018.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\3510000 ( Direct Cost: \2700000 、 Indirect Cost:\810000 )

    Primary microcephaly is partially caused by deficiencies in DNA Damage Response system (DDR system). As prevalence of these genetic disorders are very rare and the patients usually display overlapping clinical features, we often face with difficulties in the clinical diagnosis.
    In this project, we aimed to develop a system helpful in the differential diagnosis of microcephaly and similar conditions. The developed system comprises next generation DNA sequencing (NGS) as well as DDR activity assays for detecting deficiencies in double strand break (DSB) repair and nucleotide excision repair (NER).

  20. 小頭症を発症する遺伝性疾患の鑑別診断技術開発

    2016.4 - 2017.3

    科学研究費補助金  研究成果公開促進費 (研究成果公開発表)

    荻 朋男

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    Authorship:Principal investigator 

  21. 小頭症を発症する遺伝性疾患の鑑別診断技術開発

    2016.4 - 2017.3

    科学研究費助成事業  挑戦的研究(萌芽)

    荻 朋男

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2080000 ( Direct Cost: \1600000 、 Indirect Cost:\480000 )

  22. Molecular regions of BRCA proteins responsible for cancer suppression

    Grant number:15K06833  2015.4 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Takenaka Katsuya

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    Authorship:Coinvestigator(s) 

    BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. A major function of BRCA2 is known as a regulator of homologous recombination in DNA damage repair. In addition, BRCA2 also plays an important role in centrosomal regulation, whose dysfunction might be involved inthe tumorigenesis of breast cancer. Though, detail molecular mechanism was not uncovered. In the present study, we tried to locate a molecular region of BRCA2 responsible for this function. Numbers of centrosome in a cell are counted to see if an overexpression of a specific fragment of BRCA proteins could impair a numerical integrity of centrosomes. For this purpose we developed an automated centrosome-counting system based on image recognition, which allows us to judge a large number of transfected cells without human bias.

  23. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費補助金  基盤研究(A)

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    Authorship:Principal investigator 

  24. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費補助金  その他

  25. Molecular epidemiology studies on rare genetic disorders and pediatric cancer cohorts associated with genome instability

    Grant number:15H02654  2015.4 - 2018.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\42900000 ( Direct Cost: \33000000 、 Indirect Cost:\9900000 )

    Genomic DNA is constitutively exposed to various DNA damaging sources; therefore, the DNA repair and damage response system is essential for the maintenance and stable transmission of the genetic information. A failure in this system elicits genome instability and causes carcinogenesis and ageing. In this study, we have collected various hereditary disorder cases world-widely to identify genetic factors associated with congenital genome instability. We generated a pathogenic mutation database as well as a cell-bank from the analysis of collected samples. We have identified several new DNA repair genes with novel pathogenic mutations. We are currently working on the molecular pathogenesis of newly identified mutations and their associated genetic disorders.

  26. Biochemical analysis of transcription coupled nucleotide excision repair factors

    Grant number:15K00541  2015.4 - 2018.3

    KARATA Kiyonobu

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    Authorship:Coinvestigator(s) 

    The detailed function of TC-NER-specific factors, CSA, CSB and UVSSA, remains to be defined. In order to elucidate their function biochemically, we tried to reconstitute in vitro TC-NER assay system using DNA templates harboring a site-directed DNA damage. In addition, we have developed the purification method of UVSSA protein for its X-ray crystal structure analysis.

  27. The molecular epidemiological study of DNA repair-related genes in post-Chernobyl radiation-induced thyroid cancers

    Grant number:26293142  2014.4 - 2019.3

    MITSUTAKE Norisato

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    Authorship:Coinvestigator(s) 

    Mutation data were obtained by next-generation sequencing using genomic DNA of 56 post-Chernobyl radiation-induced pediatric thyroid cancer cases and 55 controls who were also lived in the same area and exposed but without development of thyroid cancer. Although several candidate genes related to carcinogenesis were found, further research is needed. No obvious accumulation of mutations was identified among DNA repair genes. Through this project, we were able to acquire comprehensive genomic data of the invaluable samples and established the basis of continuous research in future.

  28. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費補助金  基盤研究(B)

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    Authorship:Principal investigator 

  29. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費補助金  その他

  30. In vitro reconstitution of the initiation process of transcription-coupled nucleotide-excision repair

    Grant number:26291005  2014.4 - 2018.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\16640000 ( Direct Cost: \12800000 、 Indirect Cost:\3840000 )

    Transcription-coupled nucleotide-excision repair (TC-NER) is one of the versatile DNA repair process that removes major UV-induced DNA lesions from actively transcribed genes. To investigate the initiation process of TC-NER reaction, we focused on a molecular mechanism that involves DNA-damage induced ubiquitination of RNA polymerase IIo (RNA pol IIo). The process is dependent on a recently identified TC-NER factor, UVSSA.
    To determine the ubiquitination sites, we performed in vitro ubiquitination assay as well as SILAC-based High-Resolution Accurate Mass (HRAM) spectrometry. From the studies, we identified UVSSA-dependent ubiquitination sites required for the efficient TC-NER activity.

  31. Mechanism of genomic DNA damage response mediated by acetylation of non-histone proteins

    Grant number:26281026  2014.4 - 2018.3

    YASUDA Takeshi

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    We newly identified several non-histone proteins involved in DNA damage response, which are acetylated by p300 and CBP histone acetyltransferases in vitro. Among the identified acetylated proteins, we showed that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DNA double strand break (DSB) sites. We identified 13 acetylation sites in RAD52. We revealed that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, we demonstrated that the acetylation of RAD52 is linked to ATM signaling. Our findings clarify the importance of RAD52 acetylation in HR.

  32. -

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    Grant type:Competitive

  33. -

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    Grant type:Competitive

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