Faculty Profiles - OGI Tomoo

Papers - OGI Tomoo

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

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

Ecotoxicology and environmental safety Vol. 264 page： 115482 2023.10

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

Live cell transcription-coupled nucleotide excision repair dynamics revisited. Reviewed Open Access

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

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

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes. Reviewed Open Access

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

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

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

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

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

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

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

AP1B1の複合ヘテロ接合性変異によるMEDNIK-like syndrome

伊藤靖敏, 武市拓也, 竹内想, 室慶直, 秋山真志, 猪狩翔平, 森龍彦, 山本俊幸, 小野敦史, 陶山和秀, 細矢光亮, 荻朋男

角化症研究会記録集 Vol. 37 page： 22 - 25 2023.7

Utility of nanopore sequencing for detecting pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure Reviewed Open Access

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

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

A case of Cockayne syndrome with unusually mild clinical manifestations Reviewed Open Access

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Dermatology

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

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

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

BONE REPORTS Vol. 17 page： 101626 2022.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Bone Reports

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular Genetics and Metabolism Reports

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Open Forum Infectious Diseases

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.

DOI： 10.1093/ofid/ofac504

Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis Open Access

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Annals of Clinical and Translational Neurology

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.

DOI： 10.1002/acn3.51657

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Human Genetics

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.

DOI： 10.1038/s10038-022-01025-0

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

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

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

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.

DOI： 10.1016/j.jdermsci.2022.08.003

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Brain and Development

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.

DOI： 10.1016/j.braindev.2022.04.009

Whole-exome analysis of 177 pediatric patients with undiagnosed diseases Open Access

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

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.

DOI： 10.1038/s41598-022-14161-6

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