Faculty Profiles - OGI Tomoo

Papers - OGI Tomoo

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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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.18999/nagjms.83.2.393

[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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Clinical Neurology

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.

DOI： 10.5692/clinicalneurol.cn-001542

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：BMC Microbiology

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.

DOI： 10.1186/s12866-021-02154-w

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.neurobiolaging.2020.10.028

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

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

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1186/s40478-020-01099-x

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/ajmg.a.61927

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：American Association for the Advancement of Science (AAAS)

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.

DOI： 10.1126/sciadv.abd7197

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.15252/embj.2020104464

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

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

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.3389/fnmol.2020.00154

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.eplepsyres.2020.106371

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1073/pnas.1920165117

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

<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/).

DOI： 10.1093/nargab/lqaa038

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

Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.cell.2020.02.010

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/mgg3.1148

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

Language：Japanese Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jdermsci.2019.12.001

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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