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写真a

ハマナカ コウヘイ
濵中 耕平
Kohei Hamanaka
所属
医学部 医学科 遺伝学 講師
職名
講師
プロフィール

平成24年4月 京都大学大学院医学研究科 博士課程(医学専攻<臨床神経学分野>)

        (出向先:国立精神・神経医療研究センター 神経研究所 疾病研究第一部)

平成28年4月 国立精神・神経医療研究センター 神経研究所 疾病研究第一部 研究員

平成29年1月 横浜市立大学大学院医学研究科 環境分子医科学(遺伝学)研究員

令和 2年7月 横浜市立大学大学院医学研究科 環境分子医科学(遺伝学)助教

令和 5年4月 京都大学 高等研究院 ヒト生物学高等研究拠点 システムゲノム医学 特定助教

令和 7年4月 横浜市立大学大学院医学研究科 環境分子医科学(遺伝学)講師

        京都大学 高等研究院 ヒト生物学高等研究拠点 システムゲノム医学 特任講師

現在に至る

外部リンク

学位

  • 医学 ( 2016年7月   京都大学 )

研究キーワード

  • 次世代シークエンシング

  • 希少疾患遺伝学

  • 機能ゲノム学

  • オミクス解析

  • 筋病理学

  • 顔面肩甲上腕型筋ジストロフィー

  • リピート伸長病

研究分野

  • ライフサイエンス / 遺伝学

委員歴

  • Journal of Human Genetics   編集委員会  

    2024年6月 - 現在   

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  • Human Genome Variation   編集委員会  

    2024年6月 - 現在   

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論文

  • Mosaic deletions detected by genome sequencing in two families. 国際誌

    Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Nobuhiko Okamoto, Ayataka Fujimoto, Hideo Enoki, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of human genetics   2025年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Trio-based genome sequencing (GS) is useful for genetic analysis of cases in which exome sequencing failed to resolve the disease-causing variants. In this paper, we report two unrelated families with pathogenic deletions (one outside exome-covering genomic regions and the other involving a single exon) successfully identified by GS. Notably, mosaic deletions were found in both families, which were carefully evaluated in detail by analyzing GS data using Integrative Genomics Viewer, breakpoint PCR, quantitative PCR, and digital PCR. This study emphasizes the benefit of trio-based GS, enabling straightforward interpretation, further aided by other confirmatory experimental methods.

    DOI: 10.1038/s10038-025-01336-y

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  • Diagnostic utility of single-locus DNA methylation mark in Sotos syndrome developed by nanopore sequencing-based episignature. 国際誌

    Takeshi Mizuguchi, Nobuhiko Okamoto, Taiki Hara, Naoto Nishimura, Masamune Sakamoto, Li Fu, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Kazuhiko Nakabayashi, Satoko Miyatake, Naomichi Matsumoto

    Clinical epigenetics   17 ( 1 )   27 - 27   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: In various neurodevelopmental disorders (NDDs), sets of differential methylation marks (referred to as DNA methylation signatures or episignatures) are syndrome-specific and useful in evaluating the pathogenicity of detected genetic variants. These signatures have generally been tested using methylation arrays, requiring additional experimental and evaluation costs. As an alternative, long-read sequencing can simultaneously and accurately evaluate genetic and epigenetic changes. In addition, genome-wide DNA methylation profiling with more complete sets of CpG using long-read sequencing (than methylation arrays) may provide alternative but more comprehensive DNA methylation signatures, which have yet to be adequately investigated. METHODS: Nine and seven cases of molecularly diagnosed Sotos syndrome and ATR-X syndrome, respectively, were sequenced using nanopore long-read sequencing, together with 22 controls. Genome-wide differential DNA methylation analysis was performed. Among these differential DNA methylation sites, a single-locus DNA methylation mark at part of the NSD1 CpG island (CpGi) was subsequently studied in an additional 22 cases with a NSD1 point mutation or a 5q35 submicroscopic deletion involving NSD1. To investigate the potential utility of a single-locus DNA methylation test at NSD1 CpGi for differential diagnosis, nine cases with NSD1-negative clinically overlapping overgrowth intellectual disability syndromes (OGIDs) were also tested. RESULTS: Long-read sequencing enabled the successful extraction of two sets of differential methylation marks unique to each of Sotos syndrome and ATR-X syndrome, referred to as long-read-based DNA methylation signatures (LR-DNAm signatures), as alternatives to reported DNA methylation signatures (obtained by methylation array). Additionally, we found that a part, but not all, of the NSD1 CpGi were hypomethylated compared with the level in controls in both cases harboring NSD1 point mutations and those with a 5q35 submicroscopic deletion. This difference in methylation is specific to Sotos syndrome and lacking in other OGIDs. CONCLUSIONS: Simultaneous evaluation of genetic and epigenetic alterations using long-read sequencing may improve the discovery of DNA methylation signatures, which may in turn increase the diagnostic yields. As an example of the outcomes of these analyses, we propose that a single-locus DNA methylation test at NSD1 CpGi may streamline the molecular diagnosis of Sotos syndrome, regardless of the type of NSD1 aberration.

    DOI: 10.1186/s13148-025-01832-0

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  • A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis. 国際誌

    Shinji Masuko, Mitsuto Sato, Katsuya Nakamura, Kohei Hamanaka, Satoko Miyatake, Yuji Inaba, Tomoki Kosho, Naomichi Matsumoto, Yoshiki Sekijima

    Molecular genetics & genomic medicine   12 ( 11 )   e70044   2024年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Heterozygous variants of sequestosome-1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child-onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family. METHODS: We performed clinical and genetic laboratory evaluations of the two patients and their healthy parents. RESULTS: By whole-exome sequencing, we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?) in the initial codon, and c.969G>A, located at the 3' end of exon 6, which is novel and seemingly a synonymous but is actually a truncating variant causing aberrant splicing. An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA. Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy. Our patients experienced chorea during adolescence. CONCLUSIONS: Only a few reports have highlighted the presence of chorea; however, our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea. This study also demonstrates the utility of UDCs, obtained using noninvasive approaches, in functionally analyzing genetic diseases.

    DOI: 10.1002/mgg3.70044

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  • Complex chromosomal 6q rearrangements revealed by combined long-molecule genomics technologies. 国際誌

    Sachiko Ohori, Hironao Numabe, Satomi Mitsuhashi, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Atsushi Fujita, Naomichi Matsumoto

    Genomics   110894 - 110894   2024年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Technologies for detecting structural variation (SV) have advanced with the advent of long-read sequencing, which enables the validation of SV at a nucleotide level. Optical genome mapping (OGM), a technology based on physical mapping, can also provide comprehensive SVs analysis. We applied long-read whole genome sequencing (LRWGS) to accurately reconstruct breakpoint (BP) segments in a patient with complex chromosome 6q rearrangements that remained elusive by conventional karyotyping. Although all BPs were precisely identified by LRWGS, there were two possible ways to construct the BP segments in terms of their orders and orientations. Thus, we also used OGM analysis. Notably, OGM recognized entire inversions exceeding 500 kb in size, which LRWGS could not characterize. Consequently, here we successfully unveil the full genomic structure of this complex chromosomal 6q rearrangement and cryptic SVs through combined long-molecule genomic analyses, showcasing how LRWGS and OGM can complement each other in SV analysis.

    DOI: 10.1016/j.ygeno.2024.110894

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  • Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese

    Satoko Miyatake, Hiroshi Doi, Hiroaki Yaguchi, Eriko Koshimizu, Naoki Kihara, Tomoyasu Matsubara, Yasuko Mori, Kenjiro Kunieda, Yusaku Shimizu, Tomoko Toyota, Shinichi Shirai, Masaaki Matsushima, Masaki Okubo, Taishi Wada, Misako Kunii, Ken Johkura, Ryosuke Miyamoto, Yusuke Osaki, Takabumi Miyama, Mai Satoh, Atsushi Fujita, Yuri Uchiyama, Naomi Tsuchida, Kazuharu Misawa, Kohei Hamanaka, Haruka Hamanoue, Takeshi Mizuguchi, Hiroyuki Morino, Yuishin Izumi, Takayoshi Shimohata, Kunihiro Yoshida, Hiroaki Adachi, Fumiaki Tanaka, Ichiro Yabe, Naomichi Matsumoto

    Journal of Neurology, Neurosurgery & Psychiatry   jnnp - 2024   2024年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ  

    Background

    Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing ofFGF14repeat expansion to elucidate its repeat motifs and pathogenicity.

    Methods

    We screenedFGF14repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing ofFGF14repeat expansion.

    Results

    In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5′-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)<sub>≥250</sub>and (GAA)<sub>≥200</sub>were enriched in patients, whereas (GAA-GCA)<sub>≥200</sub>was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)<sub>≥200</sub>for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)<sub>≥250</sub>in the Japanese population than in Caucasians (0.15% vs 0.32%–1.26%).

    Conclusions

    FGF14repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

    DOI: 10.1136/jnnp-2024-333541

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  • Reduced histone H3K4 trimethylation in oral mucosa of patients with DYT-KMT2B. 国際誌

    Naoto Sugeno, Satoko Kumada, Hirofumi Kashii, Jun Ikezawa, Toshitaka Kawarai, Takaaki Nakamura, Ako Miyata, Shun Ishiyama, Kazuki Sato, Shun Yoshida, Hutoshi Sekiguchi, Kohei Hamanaka, Satoko Miyatake, Noriko Miyake, Naomichi Matsumoto, Hiroyuki Akagawa, Kenjiro Kosaki, Hiroshi Yoshihashi, Takafumi Hasegawa, Masashi Aoki

    Parkinsonism & related disorders   124   107018 - 107018   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples. OBJECTIVES: To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients. METHODS: A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies. RESULTS: Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups. CONCLUSIONS: Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means.

    DOI: 10.1016/j.parkreldis.2024.107018

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  • 軽度知的障害を合併したATL1遺伝子のp.Arg239Cysによる遺伝性痙性対麻痺の1例

    峯村 はる香, 山岸 裕和, 小坂 仁, 渡邉 英明, 濱中 耕平, 宮武 聡子, 松本 直通, 田島 敏広

    小児科   65 ( 2 )   189 - 192   2024年2月

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    記述言語:日本語   出版者・発行元:金原出版(株)  

    6歳男児。2歳過ぎより目立っていた尖足に対して、3歳2ヵ月時に当科へ紹介受診となった。所見では両下肢ともに尖足位で、独歩は可能であったが、膝関節を伸展させた状態で歩行していた。対処として両下肢の尖足に対して理学療法や下腿三頭筋へのボトックス注射が行われたが、5歳頃より連続歩行距離が短くなり、長距離の移動には車いすが必要となった。そこで、緩徐に進行する痙性対麻痺症状から遺伝子検査を行った結果、本症例は軽度知的障害を合併したp.Arg239Cysによる遺伝性痙性対麻痺と診断された。6歳7ヵ月時にアキレス腱延長術を行った結果、目下は連続歩行距離は500mで、疲労時や移動の際は車いすを使用している。

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00639&link_issn=&doc_id=20240305060014&doc_link_id=10.18888%2Fsh.0000002944&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsh.0000002944&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

  • Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability. 国際誌

    Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of human genetics   2024年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA). In this study, we identified novel compound heterozygous ABCA2 variants (NM_001606.5:c.[5300-17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA.

    DOI: 10.1038/s10038-024-01219-8

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  • Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling. 国際誌

    Eriko Koshimizu, Mitsuhiro Kato, Kazuharu Misawa, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto

    Journal of human genetics   2024年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter disorder caused by pathogenic DOPA decarboxylase (DDC) variants. We previously reported Japanese siblings with AADC deficiency, which was confirmed by the lack of enzyme activity; however, only a heterozygous missense variant was detected. We therefore performed targeted long-read sequencing by adaptive sampling to identify any missing variants. Haplotype phasing and variant calling identified a novel deep intronic variant (c.714+255 C > A), which was predicted to potentially activate the noncanonical splicing acceptor site. Minigene assay revealed that wild-type and c.714+255 C > A alleles had different impacts on splicing. Three transcripts, including the canonical transcript, were detected from the wild-type allele, but only the noncanonical cryptic exon was produced from the variant allele, indicating that c.714+255 C > A was pathogenic. Target long-read sequencing may be used to detect hidden pathogenic variants in unresolved autosomal recessive cases with only one disclosed hit variant.

    DOI: 10.1038/s10038-023-01217-2

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  • Long-term clinical course of adult-onset refractory epilepsy in cardiofaciocutaneous syndrome with a pathogenic MAP2K1 variant: a case report. 国際誌

    Rie Tsuburaya-Suzuki, Sachiko Ohori, Kohei Hamanaka, Atsushi Fujita, Naomichi Matsumoto, Masako Kinoshita

    Frontiers in genetics   15   1410979 - 1410979   2024年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC.

    DOI: 10.3389/fgene.2024.1410979

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  • Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders. 国際誌

    Yasuhiro Utsuno, Keisuke Hamada, Kohei Hamanaka, Keita Miyoshi, Keiji Tsuchimoto, Satoshi Sunada, Toshiyuki Itai, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Takeshi Mizuguchi, Yasuhito Kato, Kuniaki Saito, Kazuhiro Ogata, Naomichi Matsumoto

    Journal of human genetics   2023年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. Biallelic SLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in early childhood. COMNB is clinically milder and has a later onset than SMVTD, at approximately 10 years of age. COMNB symptoms are mostly limited to peripheral motor neuropathy. Here we report three patients from one Japanese family harboring novel compound heterozygous missense variants in SLC5A6, namely NM_021095.4:c.[221C>T];[642G>C] p.[(Ser74Phe)];[(Gln214His)]. Both variants were predicted to be deleterious through multiple lines of evidence, including amino acid conservation, in silico predictions of pathogenicity, and protein structure considerations. Drosophila analysis also showed c.221C>T to be pathogenic. All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities. They also had a mild motor developmental delay that almost completely resolved despite no treatment. In terms of severity, their phenotypes were intermediate between SMVTD and COMNB. From these findings we propose a new SLC5A6-related disorder, spontaneously remitting developmental delay with brain cysts (SRDDBC) whose phenotypic severity is between that of SMVTD and COMNB. Further clinical and genetic evidence is needed to support our suggestion.

    DOI: 10.1038/s10038-023-01206-5

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  • Complete SAMD12 repeat expansion sequencing in a four-generation BAFME1 family with anticipation. 国際誌

    Takeshi Mizuguchi, Tomoko Toyota, Eriko Koshimizu, Shinichi Kameyama, Hiromi Fukuda, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Hiroaki Adachi, Naomichi Matsumoto

    Journal of human genetics   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant, adult-onset neurological disease caused by SAMD12 repeat expansion. In BAFME1, anticipation, such as the earlier onset of tremor and/or seizures in the next generation, was reported. This could be explained by intergenerational repeat instability, leading to larger expansions in successive generations. We report a four-generation BAFME1-affected family with anticipation. Using Nanopore long-read sequencing, detailed information regarding the sizes, configurations, and compositions of the expanded SAMD12 repeats across generations was obtained. Unexpectedly, a grandmother-mother-daughter triad showed similar repeat structures but with slight repeat expansions, despite quite variable age of onset of seizures (range: 52-14 years old), implying a complex relationship between the SAMD12 repeat expansion sequence and anticipation. This study suggests that different factor(s) from repeat expansion could modify the anticipation in BAFME1.

    DOI: 10.1038/s10038-023-01187-5

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  • A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association

    Rie Seyama, Masashi Nishikawa, Yuri Uchiyama, Keisuke Hamada, Yuka Yamamoto, Masahiro Takeda, Takanori Ochi, Monami Kishi, Toshifumi Suzuki, Kohei Hamanaka, Atsushi Fujita, Naomi Tsuchida, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Shintaro Makino, Takashi Yao, Hidenori Ito, Atsuo Itakura, Kazuhiro Ogata, Koh-ichi Nagata, Naomichi Matsumoto

    Scientific Reports   13 ( 1 )   2023年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T &gt; C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.

    DOI: 10.1038/s41598-023-36381-0

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    その他リンク: https://www.nature.com/articles/s41598-023-36381-0

  • Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias. 国際誌

    Hiromi Fukuda, Takeshi Mizuguchi, Hiroshi Doi, Shinichi Kameyama, Misako Kunii, Hideto Joki, Tatsuya Takahashi, Hiroyasu Komiya, Mei Sasaki, Yosuke Miyaji, Sachiko Ohori, Eriko Koshimizu, Yuri Uchiyama, Naomi Tsuchida, Atsushi Fujita, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Fumiaki Tanaka, Naomichi Matsumoto

    Journal of human genetics   68 ( 10 )   689 - 697   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

    DOI: 10.1038/s10038-023-01170-0

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  • Biallelic structural variations within<i>FGF12</i>detected by long-read sequencing in epilepsy

    Sachiko Ohori, Akihiko Miyauchi, Hitoshi Osaka, Charles Marques Lourenco, Naohiro Arakaki, Toru Sengoku, Kazuhiro Ogata, Rachel Sayuri Honjo, Chong Ae Kim, Satomi Mitsuhashi, Martin C Frith, Rie Seyama, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Kuniaki Saito, Atsushi Fujita, Naomichi Matsumoto

    Life Science Alliance   6 ( 8 )   e202302025 - e202302025   2023年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Life Science Alliance, LLC  

    We discovered biallelic intragenic structural variations (SVs) inFGF12by applying long-read whole genome sequencing to an exome-negative patient with developmental and epileptic encephalopathy (DEE). We also found another DEE patient carrying a biallelic (homozygous) single-nucleotide variant (SNV) inFGF12that was detected by exome sequencing.FGF12heterozygous recurrent missense variants with gain-of-function or heterozygous entire duplication ofFGF12are known causes of epilepsy, but biallelic SNVs/SVs have never been described.FGF12encodes intracellular proteins interacting with the C-terminal domain of the alpha subunit of voltage-gated sodium channels 1.2, 1.5, and 1.6, promoting excitability by delaying fast inactivation of the channels. To validate the molecular pathomechanisms of these biallelicFGF12SVs/SNV, highly sensitive gene expression analyses using lymphoblastoid cells from the patient with biallelic SVs, structural considerations, andDrosophilain vivo functional analysis of the SNV were performed, confirming loss-of-function. Our study highlights the importance of small SVs in Mendelian disorders, which may be overlooked by exome sequencing but can be detected efficiently by long-read whole genome sequencing, providing new insights into the pathomechanisms of human diseases.

    DOI: 10.26508/lsa.202302025

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  • An integrated genetic analysis of epileptogenic brain malformed lesions

    Atsushi Fujita, Mitsuhiro Kato, Hidenori Sugano, Yasushi Iimura, Hiroharu Suzuki, Jun Tohyama, Masafumi Fukuda, Yosuke Ito, Shimpei Baba, Tohru Okanishi, Hideo Enoki, Ayataka Fujimoto, Akiyo Yamamoto, Kentaro Kawamura, Shinsuke Kato, Ryoko Honda, Tomonori Ono, Hideaki Shiraishi, Kiyoshi Egawa, Kentaro Shirai, Shinji Yamamoto, Itaru Hayakawa, Hisashi Kawawaki, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Mitsuko Nakashima, Hirotomo Saitsu, Noriko Miyake, Akiyoshi Kakita, Naomichi Matsumoto

    Acta Neuropathologica Communications   11 ( 1 )   2023年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

    DOI: 10.1186/s40478-023-01532-x

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    その他リンク: https://link.springer.com/article/10.1186/s40478-023-01532-x/fulltext.html

  • Genome-wide identification of tandem repeats associated with splicing variation across 49 tissues in humans. 国際誌

    Kohei Hamanaka, Daisuke Yamauchi, Eriko Koshimizu, Kei Watase, Kaoru Mogushi, Kinya Ishikawa, Hidehiro Mizusawa, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Kazuharu Misawa, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto

    Genome research   33 ( 3 )   435 - 447   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tandem repeats (TRs) are one of the largest sources of polymorphism, and their length is associated with gene regulation. Although previous studies reported several tandem repeats regulating gene splicing in cis (spl-TRs), no large-scale study has been conducted. In this study, we established a genome-wide catalog of 9537 spl-TRs with a total of 58,290 significant TR-splicing associations across 49 tissues (false discovery rate 5%) by using Genotype-Tissue expression (GTex) Project data. Regression models explaining splicing variation by using spl-TRs and other flanking variants suggest that at least some of the spl-TRs directly modulate splicing. In our catalog, two spl-TRs are known loci for repeat expansion diseases, spinocerebellar ataxia 6 (SCA6) and 12 (SCA12). Splicing alterations by these spl-TRs were compatible with those observed in SCA6 and SCA12. Thus, our comprehensive spl-TR catalog may help elucidate the pathomechanism of genetic diseases.

    DOI: 10.1101/gr.277335.122

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  • A novel NONO variant that causes developmental delay and cardiac phenotypes

    Toshiyuki Itai, Atsushi Sugie, Yohei Nitta, Ryuto Maki, Takashi Suzuki, Yoichi Shinkai, Yoshihiro Watanabe, Yusuke Nakano, Kazushi Ichikawa, Nobuhiko Okamoto, Yasuhiro Utsuno, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Yuri Uchiyama, Naomi Tsuchida, Noriko Miyake, Kazuharu Misawa, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto

    Scientific Reports   13 ( 1 )   2023年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C &gt; G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.

    DOI: 10.1038/s41598-023-27770-6

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    その他リンク: https://www.nature.com/articles/s41598-023-27770-6

  • Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism. 国際誌

    Rie Seyama, Yuri Uchiyama, Yosuke Kaneshi, Kohei Hamanaka, Atsushi Fujita, Naomi Tsuchida, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Shintaro Makino, Atsuo Itakura, Nobuhiko Okamoto, Naomichi Matsumoto

    Journal of human genetics   68 ( 5 )   363 - 367   2023年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    TNNI2 at 11p15.5 encodes troponin I2, fast skeletal type, which is a member of the troponin I gene family and a component of the troponin complex. Distal arthrogryposis (DA) is characterized by congenital limb contractures without primary neurological or muscular effects. DA is inherited in an autosomal dominant fashion and is clinically and genetically heterogeneous. Exome sequencing identified a causative variant in TNNI2 [NM_003282.4:c.532T>C p.(Phe178Leu)] in a Japanese girl with typical DA2b. Interestingly, the familial study using Sanger sequencing suggested a mosaic variant in her healthy father. Subsequent targeted amplicon-based deep sequencing detected the TNNI2 variant with variant allele frequencies of 9.4-17.7% in genomic DNA derived from peripheral blood leukocytes, saliva, hair, and nails in the father. We confirmed a disease-causing variant in TNNI2 in the proband inherited from her asymptomatic father with its somatic variant. Our case demonstrates that careful clinical and genetic evaluation is required in DA.

    DOI: 10.1038/s10038-022-01117-x

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  • Three <scp>KINSSHIP</scp> syndrome patients with mosaic and germline <scp> <i>AFF3</i> </scp> variants

    Yuta Inoue, Naomi Tsuchida, Nobuhiko Okamoto, Shimakawa Shuichi, Kei Ohashi, Shinji Saitoh, Atsushi Ogawa, Keisuke Hamada, Masamune Sakamoto, Noriko Miyake, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Kazuhiro Ogata, Yuri Uchiyama, Naomichi Matsumoto

    Clinical Genetics   2023年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/cge.14292

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cge.14292

  • A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8. 国際誌

    Masamune Sakamoto, Toshihide Shiiki, Shuji Matsui, Nobuhiko Okamoto, Eriko Koshimizu, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of human genetics   68 ( 4 )   247 - 253   2022年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pontocerebellar hypoplasia (PCH) is currently classified into 16 subgroups. Using mostly next-generation sequencing, pathogenic variants have been identified in as many as 24 PCH-associated genes. PCH type 8 (PCH8) is a rare heterogeneous disorder. Its clinical presentation includes severe development delay, increased muscle tone, microcephaly, and magnetic resonance imaging (MRI) abnormalities such as reduced cerebral white matter, a thin corpus callosum, and brainstem and cerebellar hypoplasia. To date, only two variants in the CHMP1A gene (MIM: 164010), NM_002768.5: c.88 C > T (p.Glu30*) and c.28-13 G > A, have been identified homozygously in seven patients with PCH8 from four families (MIM: 614961). CHMP1A is a subunit of the endosomal sorting complex required for transport III (ESCRT-III), which regulates the formation and release of extracellular vesicles. Biallelic CHMP1A loss of function impairs the ESCRT-III-mediated release of extracellular vesicles, which causes impaired progenitor proliferation in the developing brain. Herein, we report a patient with PCH8 who had a homozygous CHMP1A variant, c.122delA (p.Asn41Metfs*2), which arose from segmental uniparental disomy. Although our patient had similar MRI findings to those of previously reported patients, with no progression, we report some novel neurological and developmental findings that expand our knowledge of the clinical consequences associated with CHMP1A variants.

    DOI: 10.1038/s10038-022-01098-x

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  • [A case of generalized dystonia DYT28 with a novel de novo mutation in the KMT2B gene].

    Kenju Hara, Haruka Ouchi, Kohei Hamanaka, Satoko Miyatake, Naomichi Matsumoto

    Rinsho shinkeigaku = Clinical neurology   62 ( 11 )   856 - 859   2022年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The patient exhibited plantarflexion during walking at the age of five. He then developed writer's cramp at the age of six, dysphonia at 15 years, and action-induced dystonia with left knee elevation and trunk swinging when walking at 16 years, which subsequently spread to the right leg at 19 years. Levodopa therapy was ineffective for dystonia. Brain MRI showed no abnormalities. He was diagnosed with DYT28 after detecting a novel heterozygous mutation (c.433C>T, p.Arg145*) in the KMT2B gene using whole-exome sequencing at age 39. Furthermore, the patient's parents exhibited normal alleles, confirming the de novo status of KMT2B gene mutation. We should consider DYT28 in addition to DYT1 and DYT5 in patients who developed leg dystonia in childhood.

    DOI: 10.5692/clinicalneurol.cn-001773

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  • Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy. 国際誌

    Masamune Sakamoto, Kazuhiro Iwama, Masayuki Sasaki, Akihiko Ishiyama, Hirofumi Komaki, Takashi Saito, Eri Takeshita, Yuko Shimizu-Motohashi, Kazuhiro Haginoya, Tomoko Kobayashi, Tomohide Goto, Yu Tsuyusaki, Mizue Iai, Kenji Kurosawa, Hitoshi Osaka, Jun Tohyama, Yu Kobayashi, Nobuhiko Okamoto, Yume Suzuki, Satoko Kumada, Kenji Inoue, Hideaki Mashimo, Atsuko Arisaka, Ichiro Kuki, Harumi Saijo, Kenji Yokochi, Mitsuhiro Kato, Yuji Inaba, Yuko Gomi, Shinji Saitoh, Kentaro Shirai, Masafumi Morimoto, Yuishin Izumi, Yoriko Watanabe, Shin-Ichiro Nagamitsu, Yasunari Sakai, Shinobu Fukumura, Kazuhiro Muramatsu, Tomomi Ogata, Keitaro Yamada, Keiko Ishigaki, Kyoko Hirasawa, Konomi Shimoda, Manami Akasaka, Kosuke Kohashi, Takafumi Sakakibara, Masashi Ikuno, Noriko Sugino, Takahiro Yonekawa, Semra Gürsoy, Tayfun Cinleti, Chong Ae Kim, Keng Wee Teik, Chan Mei Yan, Muzhirah Haniffa, Chihiro Ohba, Shuuichi Ito, Hirotomo Saitsu, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Noriko Miyake, Naomichi Matsumoto

    Genetics in medicine : official journal of the American College of Medical Genetics   24 ( 12 )   2453 - 2463   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

    DOI: 10.1016/j.gim.2022.08.007

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  • Rapid and comprehensive diagnostic method for repeat expansion diseases using nanopore sequencing

    Satoko Miyatake, Eriko Koshimizu, Atsushi Fujita, Hiroshi Doi, Masaki Okubo, Taishi Wada, Kohei Hamanaka, Naohisa Ueda, Hitaru Kishida, Gaku Minase, Atsuhiro Matsuno, Minori Kodaira, Katsuhisa Ogata, Rumiko Kato, Atsuhiko Sugiyama, Ayako Sasaki, Takabumi Miyama, Mai Satoh, Yuri Uchiyama, Naomi Tsuchida, Haruka Hamanoue, Kazuharu Misawa, Kiyoshi Hayasaka, Yoshiki Sekijima, Hiroaki Adachi, Kunihiro Yoshida, Fumiaki Tanaka, Takeshi Mizuguchi, Naomichi Matsumoto

    npj Genomic Medicine   7 ( 1 )   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    We developed a diagnostic method for repeat expansion diseases using a long-read sequencer to improve currently available, low throughput diagnostic methods. We employed the real-time target enrichment system of the nanopore GridION sequencer using the adaptive sampling option, in which software-based target assignment is available without prior sample enrichment, and built an analysis pipeline that prioritized the disease-causing loci. Twenty-two patients with various neurological and neuromuscular diseases, including 12 with genetically diagnosed repeat expansion diseases and 10 manifesting cerebellar ataxia, but without genetic diagnosis, were analyzed. We first sequenced the 12 molecularly diagnosed patients and accurately confirmed expanded repeats in all with uniform depth of coverage across the loci. Next, we applied our method and a conventional method to 10 molecularly undiagnosed patients. Our method corrected inaccurate diagnoses of two patients by the conventional method. Our method is superior to conventional diagnostic methods in terms of speed, accuracy, and comprehensiveness.

    DOI: 10.1038/s41525-022-00331-y

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    その他リンク: https://www.nature.com/articles/s41525-022-00331-y

  • Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals

    Ken Saida, Reza Maroofian, Toru Sengoku, Tadahiro Mitani, Alistair T. Pagnamenta, Dana Marafi, Maha S. Zaki, Thomas J. O’Brien, Ehsan Ghayoor Karimiani, Rauan Kaiyrzhanov, Marina Takizawa, Sachiko Ohori, Huey Yin Leong, Gulsen Akay, Hamid Galehdari, Mina Zamani, Ratna Romy, Christopher J. Carroll, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Hadis Malek, Najmeh Ahangari, Hoda Tomoum, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, David Murphy, Natalia Dominik, Hasnaa M. Elbendary, Karima Rafat, Sanem Yilmaz, Seda Kanmaz, Mine Serin, Deepa Krishnakumar, Alice Gardham, Anna Maw, Tekki Sreenivasa Rao, Sarah Alsubhi, Myriam Srour, Daniela Buhas, Tamison Jewett, Rachel E. Goldberg, Hanan Shamseldin, Eirik Frengen, Doriana Misceo, Petter Strømme, José Ricardo Magliocco Ceroni, Chong Ae Kim, Gozde Yesil, Esma Sengenc, Serhat Guler, Mariam Hull, Mered Parnes, Dilek Aktas, Banu Anlar, Yavuz Bayram, Davut Pehlivan, Jennifer E. Posey, Shahryar Alavi, Seyed Ali Madani Manshadi, Hamad Alzaidan, Mohammad Al-Owain, Lama Alabdi, Ferdous Abdulwahab, Futoshi Sekiguchi, Kohei Hamanaka, Atsushi Fujita, Yuri Uchiyama, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Reem M. Elshafie, Kamran Salayev, Ulviyya Guliyeva, Fowzan S. Alkuraya, Joseph G. Gleeson, Kristin G. Monaghan, Katherine G. Langley, Hui Yang, Mahsa Motavaf, Saeid Safari, Mozhgan Alipour, Kazuhiro Ogata, André E.X. Brown, James R. Lupski, Henry Houlden, Naomichi Matsumoto

    Genetics in Medicine   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.gim.2022.09.010

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  • Patients with biallelic GGC repeat expansions in NOTCH2NLC exhibiting a typical neuronal intranuclear inclusion disease phenotype. 国際誌

    Shinichi Kameyama, Takeshi Mizuguchi, Hiroshi Doi, Shigeru Koyano, Masaki Okubo, Mikiko Tada, Hiroshi Shimizu, Hiromi Fukuda, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Kazuaki Kanai, Fumiaki Tanaka, Naomichi Matsumoto

    Genomics   114 ( 5 )   110469 - 110469   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report two patients with autosomal dominant neuronal intranuclear inclusion disease (NIID) harboring the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype. The zygosity of the entire NOTCH2NLC GGC repeat expansion and DNA methylation were comprehensively evaluated using fluorescent amplicon length PCR (AL-PCR), Southern blotting and targeted long-read sequencing, and detailed genetic/epigenetic and clinical features were described. In AL-PCR, we could not recognize the wild-type allele in both patients. Targeted long-read sequencing revealed that one patient harbored a homozygous repeat expansion. The other patient harbored compound heterozygous repeat expansions. The GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In conclusion, the biallelic GGC repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases could be completely dominant.

    DOI: 10.1016/j.ygeno.2022.110469

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  • Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome. 国際誌

    Rie Seyama, Yuri Uchiyama, José Ricard Magliocco Ceroni, Veronica Eun Hue Kim, Isabel Furquim, Rachel Sayuri Honjo, Matheus Augusto Araujo Castro, Lucas Vieira Lacerda Pires, Hiromi Aoi, Kazuhiro Iwama, Kohei Hamanaka, Atsushi Fujita, Naomi Tsuchida, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Shintaro Makino, Atsuo Itakura, Débora R Bertola, Chong Ae Kim, Naomichi Matsumoto

    Genomics   114 ( 5 )   110468 - 110468   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies suggest that transcript isoforms significantly overlap (approximately 60%) between brain tissue and Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs). Interestingly, 14 cohesion-related genes with variants that cause Cornelia de Lange Syndrome (CdLS) are highly expressed in the brain and LCLs. In this context, we first performed RNA sequencing of LCLs from 22 solved (with pathogenic variants) and 19 unsolved (with no confirmed variants) CdLS cases. Next, an RNA sequencing pipeline was developed using solved cases with two different methods: short variant analysis (for single-nucleotide and indel variants) and aberrant splicing detection analysis. Then, 19 unsolved cases were subsequently applied to our pipeline, and four pathogenic variants in NIPBL (one inframe deletion and three intronic variants) were newly identified. Two of three intronic variants were located at Alu elements in deep-intronic regions, creating cryptic exons. RNA sequencing with LCLs was useful for identifying hidden variants in exome-negative cases.

    DOI: 10.1016/j.ygeno.2022.110468

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  • 意識障害と原因不明の慢性硬膜下血腫を発症したVAMP2遺伝子異常症の1例

    大原 智子, 濱中 耕平, 中島 光子, 白井 育子, 有坂 敦子, 田村 友美恵, 眞下 秀明, 柏井 洋文, 星野 愛, 福田 光成, 熊田 聡子, 松本 直通, 加藤 光広

    脳と発達   54 ( 4 )   293 - 293   2022年7月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology. 国際誌

    Koyo Tsujikawa, Kohei Hamanaka, Yuichi Riku, Yuki Hattori, Norikazu Hara, Yohei Iguchi, Shinsuke Ishigaki, Atsushi Hashizume, Satoko Miyatake, Satomi Mitsuhashi, Yu Miyazaki, Mayumi Kataoka, Li Jiayi, Keizo Yasui, Satoshi Kuru, Haruki Koike, Kenta Kobayashi, Naruhiko Sahara, Norio Ozaki, Mari Yoshida, Akiyoshi Kakita, Yuko Saito, Yasushi Iwasaki, Akinori Miyashita, Takeshi Iwatsubo, Takeshi Ikeuchi, Takaki Miyata, Gen Sobue, Naomichi Matsumoto, Kentaro Sahashi, Masahisa Katsuno

    Science advances   8 ( 21 )   eabm5029   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

    DOI: 10.1126/sciadv.abm5029

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  • Monogenic causes of pigmentary mosaicism. 査読 国際誌

    Ken Saida, Pin Fee Chong, Asuka Yamaguchi, Naka Saito, Hajime Ikehara, Eriko Koshimizu, Rie Miyata, Akira Ishiko, Kazuyuki Nakamura, Hidenori Ohnishi, Kei Fujioka, Takafumi Sakakibara, Hideo Asada, Kohei Ogawa, Kyoko Kudo, Eri Ohashi, Michiko Kawai, Yuichi Abe, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Mitsuhiro Kato, Ryutaro Kira, Naomichi Matsumoto

    Human genetics   141 ( 11 )   1771 - 1784   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism.

    DOI: 10.1007/s00439-022-02437-w

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  • Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome. 国際誌

    Satoko Miyatake, Kunihiro Yoshida, Eriko Koshimizu, Hiroshi Doi, Mitsunori Yamada, Yosuke Miyaji, Naohisa Ueda, Jun Tsuyuzaki, Minori Kodaira, Hiroyuki Onoue, Masataka Taguri, Shintaro Imamura, Hiromi Fukuda, Kohei Hamanaka, Atsushi Fujita, Mai Satoh, Takabumi Miyama, Nobuko Watanabe, Yusuke Kurita, Masaki Okubo, Kenichi Tanaka, Hitaru Kishida, Shigeru Koyano, Tatsuya Takahashi, Yoya Ono, Kazuhiro Higashida, Nobuaki Yoshikura, Katsuhisa Ogata, Rumiko Kato, Naomi Tsuchida, Yuri Uchiyama, Noriko Miyake, Takayoshi Shimohata, Fumiaki Tanaka, Takeshi Mizuguchi, Naomichi Matsumoto

    Brain : a journal of neurology   145 ( 3 )   1139 - 1150   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

    DOI: 10.1093/brain/awab363

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  • Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants. 国際誌

    Kohei Hamanaka, Noriko Miyake, Takeshi Mizuguchi, Satoko Miyatake, Yuri Uchiyama, Naomi Tsuchida, Futoshi Sekiguchi, Satomi Mitsuhashi, Yoshinori Tsurusaki, Mitsuko Nakashima, Hirotomo Saitsu, Kohei Yamada, Masamune Sakamoto, Hiromi Fukuda, Sachiko Ohori, Ken Saida, Toshiyuki Itai, Yoshiteru Azuma, Eriko Koshimizu, Atsushi Fujita, Biray Erturk, Yoko Hiraki, Gaik-Siew Ch'ng, Mitsuhiro Kato, Nobuhiko Okamoto, Atsushi Takata, Naomichi Matsumoto

    Genome medicine   14 ( 1 )   40 - 40   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. METHODS: We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). RESULTS: We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 "plausible" candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. CONCLUSIONS: We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.

    DOI: 10.1186/s13073-022-01042-w

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  • Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. 国際誌

    Kohei Hamanaka, Keita Miyoshi, Jia-Hui Sun, Keisuke Hamada, Takao Komatsubara, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Takeshi Mizuguchi, Benedicte Gerard, Allan Bayat, Berardo Rinaldi, Mitsuhiro Kato, Jun Tohyama, Kazuhiro Ogata, Yun Stone Shi, Kuniaki Saito, Satoko Miyatake, Naomichi Matsumoto

    Human genetics   141 ( 2 )   283 - 293   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.

    DOI: 10.1007/s00439-021-02416-7

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  • Severe cardiac defect in Cornelia de Lange syndrome from a novel SMC1A variant. 国際誌

    Yutaka Odanaka, Akira Ashida, Shintaro Nemoto, Kohei Hamanaka, Naomichi Matsumoto

    Pediatrics international : official journal of the Japan Pediatric Society   64 ( 1 )   e15031   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ped.15031

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  • Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia. 国際誌

    Kana Kitayama, Tomoya Ishiguro, Masaki Komiyama, Takayuki Morisaki, Hiroko Morisaki, Gaku Minase, Kohei Hamanaka, Satoko Miyatake, Naomichi Matsumoto, Masaru Kato, Toru Takahashi, Tohru Yorifuji

    BMC medical genomics   14 ( 1 )   288 - 288   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. METHODS: Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon-intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. RESULTS: In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5-10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8-10 tended to be shared by multiple (2-7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. CONCLUSIONS: In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

    DOI: 10.1186/s12920-021-01139-y

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  • Father-to-offspring transmission of extremely long NOTCH2NLC repeat expansions with contractions: genetic and epigenetic profiling with long-read sequencing. 国際誌

    Hiromi Fukuda, Daisuke Yamaguchi, Kristofor Nyquist, Yasushi Yabuki, Satoko Miyatake, Yuri Uchiyama, Kohei Hamanaka, Ken Saida, Eriko Koshimizu, Naomi Tsuchida, Atsushi Fujita, Satomi Mitsuhashi, Kazuyuki Ohbo, Yuki Satake, Jun Sone, Hiroshi Doi, Keisuke Morihara, Tomoko Okamoto, Yuji Takahashi, Aaron M Wenger, Norifumi Shioda, Fumiaki Tanaka, Naomichi Matsumoto, Takeshi Mizuguchi

    Clinical epigenetics   13 ( 1 )   204 - 204   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: GGC repeat expansions in NOTCH2NLC are associated with neuronal intranuclear inclusion disease. Very recently, asymptomatic carriers with NOTCH2NLC repeat expansions were reported. In these asymptomatic individuals, the CpG island in NOTCH2NLC is hypermethylated, suggesting that two factors repeat length and DNA methylation status should be considered to evaluate pathogenicity. Long-read sequencing can be used to simultaneously profile genomic and epigenomic alterations. We analyzed four sporadic cases with NOTCH2NLC repeat expansion and their phenotypically normal parents. The native genomic DNA that retains base modification was sequenced on a per-trio basis using both PacBio and Oxford Nanopore long-read sequencing technologies. A custom workflow was developed to evaluate DNA modifications. With these two technologies combined, long-range DNA methylation information was integrated with complete repeat DNA sequences to investigate the genetic origins of expanded GGC repeats in these sporadic cases. RESULTS: In all four families, asymptomatic fathers had longer expansions (median: 522, 390, 528 and 650 repeats) compared with their affected offspring (median: 93, 117, 162 and 140 repeats, respectively). These expansions are much longer than the disease-causing range previously reported (in general, 41-300 repeats). Repeat lengths were extremely variable in the father, suggesting somatic mosaicism. Instability is more frequent in alleles with uninterrupted pure GGCs. Single molecule epigenetic analysis revealed complex DNA methylation patterns and epigenetic heterogeneity. We identified an aberrant gain-of-methylation region (2.2 kb in size beyond the CpG island and GGC repeats) in asymptomatic fathers. This methylated region was unmethylated in the normal allele with bilateral transitional zones with both methylated and unmethylated CpG dinucleotides, which may be protected from methylation to ensure NOTCH2NLC expression. CONCLUSIONS: We clearly demonstrate that the four sporadic NOTCH2NLC-related cases are derived from the paternal GGC repeat contraction associated with demethylation. The entire genetic and epigenetic landscape of the NOTCH2NLC region was uncovered using the custom workflow of long-read sequence data, demonstrating the utility of this method for revealing epigenetic/mutational changes in repetitive elements, which are difficult to characterize by conventional short-read/bisulfite sequencing methods. Our approach should be useful for biomedical research, aiding the discovery of DNA methylation abnormalities through the entire genome.

    DOI: 10.1186/s13148-021-01192-5

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  • Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms. 国際誌

    Rie Seyama, Naomi Tsuchida, Yasuyuki Okada, Sonoko Sakata, Keisuke Hamada, Yoshiteru Azuma, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Shintaro Makino, Atsuo Itakura, Satoshi Okada, Nobuhiko Okamoto, Kazuhiro Ogata, Yuri Uchiyama, Naomichi Matsumoto

    Journal of human genetics   67 ( 3 )   157 - 164   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    TET3 at 2p13.1 encodes tet methylcytosine dioxygenase 3, a demethylation enzyme that converts 5-methylcytosine to 5-hydroxymethylcytosine. Beck et al. reported that patients with TET3 abnormalities in either an autosomal dominant or recessive inheritance fashion clinically showed global developmental delay, intellectual disability, and dysmorphisms. In this study, exome sequencing identified both mono- and biallelic TET3 variants in two families: a de novo variant NM_001287491.1:c.3028 A > G:p.(Asn1010Asp), and compound heterozygous variants NM_001287491.1:c.[2077 C > T];[2896 T > G],p.[Gln693*];[Cys966Gly]. Despite the different inheritance modes, the affected individuals showed similar phenotypic features. Including these three patients, only 14 affected individuals have been reported to date. The accumulation of data regarding individuals with TET3-related disorder is necessary to describe their clinical spectrum.

    DOI: 10.1038/s10038-021-00986-y

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  • Pathogenic variants in the SMN complex gene GEMIN5 cause cerebellar atrophy. 国際誌

    Ken Saida, Junya Tamaoki, Masayuki Sasaki, Muzhirah Haniffa, Eriko Koshimizu, Toru Sengoku, Hiroki Maeda, Masahiro Kikuchi, Haruna Yokoyama, Masamune Sakamoto, Kazuhiro Iwama, Futoshi Sekiguchi, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Kazuhiro Ogata, Noriko Miyake, Satoko Miyatake, Makoto Kobayashi, Naomichi Matsumoto

    Clinical genetics   100 ( 6 )   722 - 730   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5, encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G>A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant model strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy.

    DOI: 10.1111/cge.14066

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  • Biallelic null variants in ZNF142 cause global developmental delay with familial epilepsy and dysmorphic features. 国際誌

    Shinichi Kameyama, Takeshi Mizuguchi, Hiromi Fukuda, Lip Hen Moey, Wee Teik Keng, Nobuhiko Okamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Naomichi Matsumoto

    Journal of human genetics   67 ( 3 )   169 - 173   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Biallelic variants in ZNF142 at 2q35, which encodes zinc-finger protein 142, cause neurodevelopmental disorder with seizures or dystonia. We identified compound heterozygous null variants in ZNF142, NM_001105537.4:c.[1252C>T];[1274-2A>G],p.[Arg418*];[Glu426*], in Malaysian siblings suffering from global developmental delay with epilepsy and dysmorphism. cDNA analysis showed the marked reduction of ZNF142 transcript level through nonsense-mediated mRNA decay by these novel biallelic variants. The affected siblings present with global developmental delay and epilepsy in common, which were previously described, as well as dysmorphism, which was not recognized. It is important to collect patients with ZNF142 abnormality to define its phenotypic spectrum.

    DOI: 10.1038/s10038-021-00978-y

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  • De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality. 国際誌

    Masamune Sakamoto, Kazunori Sasaki, Atsushi Sugie, Yohei Nitta, Tetsuaki Kimura, Semra Gürsoy, Tayfun Cinleti, Mizue Iai, Toru Sengoku, Kazuhiro Ogata, Atsushi Suzuki, Nobuhiko Okamoto, Kazuhiro Iwama, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Masataka Taguri, Shuuichi Ito, Hidehisa Takahashi, Noriko Miyake, Naomichi Matsumoto

    Human molecular genetics   31 ( 1 )   69 - 81   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy, and brain abnormalities, there were differences in severity, clinical course, and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).

    DOI: 10.1093/hmg/ddab224

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  • Prenatal clinical manifestations in individuals with COL4A1/2 variants. 国際誌

    Toshiyuki Itai, Satoko Miyatake, Masataka Taguri, Fumihito Nozaki, Masayasu Ohta, Hitoshi Osaka, Masafumi Morimoto, Tomoko Tandou, Fumikatsu Nohara, Yuichi Takami, Fumitaka Yoshioka, Shoko Shimokawa, Jiu Okuno-Yuguchi, Mitsuo Motobayashi, Yuko Takei, Tetsuhiro Fukuyama, Satoko Kumada, Yohane Miyata, Chikako Ogawa, Yuki Maki, Noriko Togashi, Teruyuki Ishikura, Makoto Kinoshita, Yusuke Mitani, Yonehiro Kanemura, Tsuyoshi Omi, Naoki Ando, Ayako Hattori, Shinji Saitoh, Yukihiro Kitai, Satori Hirai, Hiroshi Arai, Fumihiko Ishida, Hidetoshi Taniguchi, Yasuji Kitabatake, Keiichi Ozono, Shin Nabatame, Robert Smigiel, Mitsuhiro Kato, Koichi Tanda, Yoshihiko Saito, Akihiko Ishiyama, Yushi Noguchi, Mazumi Miura, Takaaki Nakano, Keiko Hirano, Ryoko Honda, Ichiro Kuki, Jun-Ichi Takanashi, Akihito Takeuchi, Tatsuya Fukasawa, Chizuru Seiwa, Atsuko Harada, Yusuke Yachi, Hiroyuki Higashiyama, Hiroshi Terashima, Tadayuki Kumagai, Satoshi Hada, Yoshiichi Abe, Etsuko Miyagi, Yuri Uchiyama, Atsushi Fujita, Eri Imagawa, Yoshiteru Azuma, Kohei Hamanaka, Eriko Koshimizu, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Yoshinori Tsurusaki, Hiroshi Doi, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto

    Journal of medical genetics   58 ( 8 )   505 - 513   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

    DOI: 10.1136/jmedgenet-2020-106896

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  • Spastic paraplegia-46の1例

    横井 美央, 岩中 行己男, 成毛 哲思, 濱中 耕平, 宮武 聡子, 松本 直通, 荒川 修治, 岡田 和将, 足立 弘明

    臨床神経学   61 ( 8 )   572 - 572   2021年8月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Novel CLTC variants cause new brain and kidney phenotypes. 国際誌

    Toshiyuki Itai, Satoko Miyatake, Naomi Tsuchida, Ken Saida, Sho Narahara, Yu Tsuyusaki, Matheus Augusto Araujo Castro, Chong Ae Kim, Nobuhiko Okamoto, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of human genetics   67 ( 1 )   1 - 7   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heterozygous variants in CLTC, which encode the clathrin heavy chain protein, cause neurodevelopmental delay of varying severity, and often accompanied by dysmorphic features, seizures, hypotonia, and ataxia. To date, 28 affected individuals with CLTC variants have been reported, although their phenotypes have not been fully elucidated. Here, we report three novel de novo CLTC (NM_001288653.1) variants in three individuals with previously unreported clinical symptoms: c.3662_3664del:p.(Leu1221del) in individual 1, c.2878T>C:p.(Trp960Arg) in individual 2, and c.2430+1G>T:p.(Glu769_Lys810del) in individual 3. Consistent with previous reports, individuals with missense or small in-frame variants were more severely affected. Unreported symptoms included a brain defect (cystic lesions along the lateral ventricles of the brain in individuals 1 and 3), kidney findings (high-echogenic kidneys in individual 1 and agenesis of the left kidney and right vesicoureteral reflux in individual 3), respiratory abnormality (recurrent pneumonia in individual 1), and abnormal hematological findings (anemia in individual 1 and pancytopenia in individual 3). Of note, individual 1 even exhibited prenatal abnormality (fetal growth restriction, cystic brain lesions, high-echogenic kidneys, and a heart defect), suggesting that CLTC variants should be considered when abnormal prenatal findings in multiple organs are detected.

    DOI: 10.1038/s10038-021-00957-3

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  • Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder. 国際誌

    Masaki Nishioka, An-A Kazuno, Takumi Nakamura, Naomi Sakai, Takashi Hayama, Kumiko Fujii, Koji Matsuo, Atsuko Komori, Mizuho Ishiwata, Yoshinori Watanabe, Takashi Oka, Nana Matoba, Muneko Kataoka, Ahmed N Alkanaq, Kohei Hamanaka, Takashi Tsuboi, Toru Sengoku, Kazuhiro Ogata, Nakao Iwata, Masashi Ikeda, Naomichi Matsumoto, Tadafumi Kato, Atsushi Takata

    Nature communications   12 ( 1 )   3750 - 3750   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.

    DOI: 10.1038/s41467-021-23453-w

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  • Refinement of the clinical variant interpretation framework by statistical evidence and machine learning 査読 国際誌

    Atsushi Takata, Kohei Hamanaka, Naomichi Matsumoto

    Med   2 ( 5 )   611 - 632   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation are used widely in clinical genetics, there is room for improvement of these knowledge-based guidelines. METHODS: Statistical assessment of average deleteriousness of start-lost, stop-lost, and in-frame insertion and deletion (indel) variants and extraction of deleterious subsets was performed, being informed by proportions of rare variants in the general population of the Genome Aggregation Database (gnomAD). A machine learning-based model scoring the pathogenicity of start-lost variants (the PoStaL model) was constructed by predicting possible translation initiation sites on transcripts by deep learning and training a random forest on known pathogenic and likely benign variants. FINDINGS: The proportion of rare variants was highest in stop-lost variants, followed by in-frame indels and start-lost variants, suggesting that the criteria in the ACMG/AMP guidelines assigning PVS (pathogenic very strong) to start-lost variants and PM (pathogenic moderate) to stop-lost and in-frame indel variants would not be appropriate. Regarding deleterious subsets, stop-lost variants introducing extensions of more than 30 amino acids and in-frame indels computationally predicted to be damaging are enriched for rare and known pathogenic variants. For start-lost variants, we developed the PoStaL model, which outperforms existing tools. We also provide comprehensive lists of the PoStaL scores for start-lost variants and the length of extended amino acids by stop-lost variants. CONCLUSIONS: Our study could contribute to refinement of the ACMG/AMP guidelines, provides resources for future investigation, and provides an example of how to improve knowledge-based frameworks by data-driven approaches. FUNDING: The study was supported by grants from the Japan Agency for Medical Research and Development (AMED) and the Japan Society for the Promotion of Science (JSPS).

    DOI: 10.1016/j.medj.2021.02.003

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  • De novo ATP1A3 variants cause polymicrogyria. 国際誌

    Satoko Miyatake, Mitsuhiro Kato, Takuma Kumamoto, Tomonori Hirose, Eriko Koshimizu, Takaaki Matsui, Hideyuki Takeuchi, Hiroshi Doi, Keisuke Hamada, Mitsuko Nakashima, Kazunori Sasaki, Akio Yamashita, Atsushi Takata, Kohei Hamanaka, Mai Satoh, Takabumi Miyama, Yuri Sonoda, Momoko Sasazuki, Hiroyuki Torisu, Toshiro Hara, Yasunari Sakai, Yushi Noguchi, Mazumi Miura, Yoko Nishimura, Kazuyuki Nakamura, Hideyuki Asai, Nodoka Hinokuma, Fuyuki Miya, Tatsuhiko Tsunoda, Masami Togawa, Yukihiro Ikeda, Nobusuke Kimura, Kaoru Amemiya, Asako Horino, Masataka Fukuoka, Hiroko Ikeda, Goni Merhav, Nina Ekhilevitch, Masaki Miura, Takeshi Mizuguchi, Noriko Miyake, Atsushi Suzuki, Shouichi Ohga, Hirotomo Saitsu, Hidehisa Takahashi, Fumiaki Tanaka, Kazuhiro Ogata, Chiaki Ohtaka-Maruyama, Naomichi Matsumoto

    Science advances   7 ( 13 )   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

    DOI: 10.1126/sciadv.abd2368

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  • De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy

    Toshiyuki Itai, Kohei Hamanaka, Kazunori Sasaki, Matias Wagner, Urania Kotzaeridou, Ines Brösse, Markus Ries, Yu Kobayashi, Jun Tohyama, Mitsuhiro Kato, Winnie P. Ong, Hui B. Chew, Kavitha Rethanavelu, Emmanuelle Ranza, Xavier Blanc, Yuri Uchiyama, Naomi Tsuchida, Atsushi Fujita, Yoshiteru Azuma, Eriko Koshimizu, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hidehisa Takahashi, Etsuko Miyagi, Yoshinori Tsurusaki, Hiroshi Doi, Masataka Taguri, Stylianos E. Antonarakis, Mitsuko Nakashima, Hirotomo Saitsu, Satoko Miyatake, Naomichi Matsumoto

    Human Mutation   42 ( 1 )   66 - 76   2021年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/humu.24130

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/humu.24130

  • Efficient detection of copy‐number variations using exome data: Batch‐ and sex‐based analyses

    Yuri Uchiyama, Daisuke Yamaguchi, Kazuhiro Iwama, Satoko Miyatake, Kohei Hamanaka, Naomi Tsuchida, Hiromi Aoi, Yoshiteru Azuma, Toshiyuki Itai, Ken Saida, Hiromi Fukuda, Futoshi Sekiguchi, Tomohiro Sakaguchi, Ming Lei, Sachiko Ohori, Masamune Sakamoto, Mitsuhiro Kato, Takayoshi Koike, Yukitoshi Takahashi, Koichi Tanda, Yuki Hyodo, Rachel S. Honjo, Debora Romeo Bertola, Chong Ae Kim, Masahide Goto, Tetsuya Okazaki, Hiroyuki Yamada, Yoshihiro Maegaki, Hitoshi Osaka, Lock‐Hock Ngu, Ch'ng G. Siew, Keng W. Teik, Manami Akasaka, Hiroshi Doi, Fumiaki Tanaka, Tomohide Goto, Long Guo, Shiro Ikegawa, Kazuhiro Haginoya, Muzhirah Haniffa, Nozomi Hiraishi, Yoko Hiraki, Satoru Ikemoto, Atsuro Daida, Shin‐ichiro Hamano, Masaki Miura, Akihiko Ishiyama, Osamu Kawano, Akane Kondo, Hiroshi Matsumoto, Nobuhiko Okamoto, Tohru Okanishi, Yukimi Oyoshi, Eri Takeshita, Toshifumi Suzuki, Yoshiyuki Ogawa, Hiroshi Handa, Yayoi Miyazono, Eriko Koshimizu, Atsushi Fujita, Atsushi Takata, Noriko Miyake, Takeshi Mizuguchi, Naomichi Matsumoto

    Human Mutation   42 ( 1 )   50 - 65   2021年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/humu.24129

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/humu.24129

  • Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing. 国際誌

    Takeshi Mizuguchi, Nobuhiko Okamoto, Keiko Yanagihara, Satoko Miyatake, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Atsushi Fujita, Noriko Miyake, Naomichi Matsumoto

    Genomics   113 ( 1 Pt 2 )   1044 - 1053   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report monozygotic twin girls with syndromic intellectual disability who underwent exome sequencing but with negative pathogenic variants. To search for variants that are unrecognized by exome sequencing, high-fidelity long-read genome sequencing (HiFi LR-GS) was applied. A 12-kb copy-neutral inversion was precisely identified by HiFi LR-GS after trio-based variant filtering. This inversion directly disrupted two genes, CPNE9 and BRPF1, the latter of which attracted our attention because pathogenic BRPF1 variants have been identified in autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP), which later turned out to be clinically found in the twins. Trio-based HiFi LR-GS together with haplotype phasing revealed that the 12-kb inversion occurred de novo on the maternally transmitted chromosome. This study clearly indicates that submicroscopic copy-neutral inversions are important but often uncharacterized culprits in monogenic disorders and that long-read sequencing is highly advantageous for detecting such inversions involved in genetic diseases.

    DOI: 10.1016/j.ygeno.2020.10.038

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  • Whole exome sequencing of fetal structural anomalies detected by ultrasonography

    Hiromi Aoi, Takeshi Mizuguchi, Toshifumi Suzuki, Shintaro Makino, Yuka Yamamoto, Jun Takeda, Yojiro Maruyama, Rie Seyama, Shiori Takeuchi, Yuri Uchiyama, Yoshiteru Azuma, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Satomi Mitsuhashi, Atsushi Takata, Noriko Miyake, Satoru Takeda, Atsuo Itakura, Naomichi Matsumoto

    Journal of Human Genetics   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1038/s10038-020-00869-8

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    その他リンク: http://www.nature.com/articles/s10038-020-00869-8

  • Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with NEXMIF Mutation: Case Report. 国際誌

    Masashi Ogasawara, Eiji Nakagawa, Eri Takeshita, Kohei Hamanaka, Satoko Miyatake, Naomichi Matsumoto, Masayuki Sasaki

    Molecular syndromology   11 ( 4 )   232 - 237   2020年11月

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    記述言語:英語  

    The NEXMIF (KIAA2022) gene is located in the X chromosome, and hemizygous mutations in NEXMIF cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in NEXMIF also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with NEXMIF mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in NEXMIF. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with NEXMIF mutations.

    DOI: 10.1159/000510172

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  • The identification of two pathogenic variants in a family with mild and severe forms of developmental delay

    Noriko Miyake, Shermineh Heydari, Masoud Garshasbi, Shinji Saitoh, Jafar Nasiri, Kohei Hamanaka, Atsushi Takata, Naomichi Matsumoto, Farnaz Hosseini Beheshti, Ahmad Reza Salehi Chaleshtori

    Journal of Human Genetics   2020年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1038/s10038-020-0809-8

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    その他リンク: http://www.nature.com/articles/s10038-020-0809-8

  • MYRFは46,XXおよび46,XY DSDの原因遺伝子である

    増永 陽平, 濱中 耕平, 高田 篤, 和田 友香, 福井 由宇子, 南 佐和子, 深見 真紀, 長谷川 奉延, 松本 直通, 緒方 勤

    日本内分泌学会雑誌   96 ( 1 )   263 - 263   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy. 査読 国際誌

    Kohei Hamanaka, Darina Šikrová, Satomi Mitsuhashi, Hiroki Masuda, Yukari Sekiguchi, Atsuhiko Sugiyama, Kazumoto Shibuya, Richard J L F Lemmers, Remko Goossens, Megumu Ogawa, Koji Nagao, Chikashi Obuse, Satoru Noguchi, Yukiko K Hayashi, Satoshi Kuwabara, Judit Balog, Ichizo Nishino, Silvère M van der Maarel

    Neurology   94 ( 23 )   e2441-e2447   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2. METHODS: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies. RESULTS: A homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression. CONCLUSION: LRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

    DOI: 10.1212/WNL.0000000000009617

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  • A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction. 査読 国際誌

    Masamune Sakamoto, Den Kouhei, Muzhirah Haniffa, Sebastián Silva, Mónica Troncoso, Paola Santander, Valeria Schonstedt, Ximena Stecher, Nobuhiko Okamoto, Kohei Hamanaka, Takeshi Mizuguchi, Satomi Mitsuhashi, Noriko Miyake, Naomichi Matsumoto

    Journal of human genetics   65 ( 9 )   751 - 757   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.

    DOI: 10.1038/s10038-020-0765-3

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  • De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy. 査読 国際誌

    Kohei Hamanaka, Eri Imagawa, Eriko Koshimizu, Satoko Miyatake, Jun Tohyama, Takanori Yamagata, Akihiko Miyauchi, Nina Ekhilevitch, Fumio Nakamura, Takeshi Kawashima, Yoshio Goshima, Ahmad Rithauddin Mohamed, Gaik-Siew Ch'ng, Atsushi Fujita, Yoshiteru Azuma, Ken Yasuda, Shintaro Imamura, Mitsuko Nakashima, Hirotomo Saitsu, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Naomichi Matsumoto

    American journal of human genetics   2020年3月

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    記述言語:英語  

    De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.

    DOI: 10.1016/j.ajhg.2020.02.011

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  • Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities. 査読

    Miyake N, Takahashi H, Nakamura K, Isidor B, Hiraki Y, Koshimizu E, Shiina M, Sasaki K, Suzuki H, Abe R, Kimura Y, Akiyama T, Tomiza S, Hirose T, Hamanaka K, Miyatake S, Mitsuhashi S, Mizuguchi T, Takata A, Oho K, Kato M, Ogata K, Matsumoto N

    Am J Hum Genet.   106 ( 1 )   13 - 25   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients. 査読 国際誌

    Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, Isidor B, Ong WP, Haniffa M, White SM, Matsuo M, Saito K, Phadke S, Kosho T, Yap P, Goyal M, Clarke LA, Sachdev R, McGillivray G, Leventer RJ, Patel C, Yamagata T, Osaka H, Hisaeda Y, Ohashi H, Shimizu K, Nagasaki K, Hamada J, Dateki S, Sato T, Chinen Y, Awaya T, Kato T, Iwanaga K, Kawai M, Matsuoka T, Shimoji Y, Tan TY, Kapoor S, Gregersen N, Rossi M, Marie-Laure M, McGregor L, Oishi K, Mehta L, Gillies G, Lockhart PJ, Pope K, Shukla A, Girisha KM, Abdel-Salam GMH, Mowat D, Coman D, Kim OH, Cordier MP, Gibson K, Milunsky J, Liebelt J, Cox H, El Chehadeh S, Toutain A, Saida K, Aoi H, Minase G, Tsuchida N, Iwama K, Uchiyama Y, Suzuki T, Hamanaka K, Azuma Y, Fujita A, Imagawa E, Koshimizu E, Takata A, Mitsuhashi S, Miyatake S, Mizuguchi T, Miyake N, Matsumoto N

    J Hum Genet.   64 ( 12 )   1173 - 1186   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s10038-019-0667-4

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  • Phenotype-genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms. 査読 国際誌

    Wakaba Endo, Satoru Ikemoto, Noriko Togashi, Takuya Miyabayashi, Erika Nakajima, Shin-Ichiro Hamano, Moriei Shibuya, Ryo Sato, Yusuke Takezawa, Yukimune Okubo, Takehiko Inui, Mitsuhiro Kato, Toru Sengoku, Kazuhiro Ogata, Kohei Hamanaka, Takeshi Mizuguchi, Satoko Miyatake, Mitsuko Nakashima, Naomichi Matsumoto, Kazuhiro Haginoya

    Brain & development   2019年11月

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    記述言語:英語  

    We report the first three Japanese patients with missense variants in the GNB1 gene. Patients exhibited severe dyskinetic quadriplegia with cortical blindness and epileptic spasms, West syndrome (but with good outcomes), and hypotonic quadriplegia that later developed into spastic diplegia. Whole-exome sequencing revealed two recurrent GNB1 variants (p.Leu95Pro and p.Ile80Thr) and one novel variant (p.Ser74Leu). A recent investigation revealed large numbers of patients with GNB1 variants. Functional studies of such variants and genotype-phenotype correlation are required to enable future precision medicine.

    DOI: 10.1016/j.braindev.2019.10.006

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  • Comparison of mitochondrial DNA variants detection using short- and long-read sequencing. 査読

    Alkanaq AN, Hamanaka K, Sekiguchi F, Taguri M, Takata A, Miyake N, Miyatake S, Mizuguchi T, Matsumoto N

    J Hum Genet.   64 ( 11 )   1107 - 1116   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome. 査読 国際誌

    Aoi H, Mizuguchi T, Ceroni JR, Kim VEH, Furquim I, Honjo RS, Iwaki T, Suzuki T, Sekiguchi F, Uchiyama Y, Azuma Y, Hamanaka K, Koshimizu E, Miyatake S, Mitsuhashi S, Takata A, Miyake N, Takeda S, Itakura A, Bertola DR, Kim CA, Matsumoto N

    J Hum Genet.   64 ( 10 )   967 - 978   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s10038-019-0643-z

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  • L-dopa反応性のジストニアを呈し、遺伝子解析によりセピアプテリン還元酵素(SR)欠損症と診断した1例(第136回静岡地方会発表症例の続報) 査読

    久世 崇史, 中釜 悠, 濱中 耕平, 新宅 治夫, 宮武 聡子, 松本 直通, 安藤 太郎, 高見澤 幸一, 入倉 朋也, 増井 礼子, 柏井 洋文, 清水 信隆, 三牧 正和

    日本小児科学会雑誌   123 ( 9 )   1450 - 1450   2019年9月

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

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  • A missense variant of SMC1A causes periodic pharmaco-resistant cluster seizures similar to PCDH19-related epilepsy. 査読

    Oguni H, Nishikawa A, Sato Y, Otani Y, Ito S, Nagata S, Kato M, Hamanaka K, Miyatake S, Matsumoto N

    Epilepsy research   155   106149   2019年9月

  • Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant. 査読 国際誌

    Uchiyama Y, Kim CA, Pastorino AC, Ceroni J, Lima PP, de Barros Dorna M, Honjo RS, Bertola D, Hamanaka K, Fujita A, Mitsuhashi S, Miyatake S, Takata A, Miyake N, Mizuguchi T, Matsumoto N

    J Hum Genet.   94 ( 9 )   955 - 960   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s10038-019-0631-3

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  • Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. 査読 国際誌

    Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, Koike H, Hashiguchi A, Takashima H, Sugiyama H, Kohno Y, Takiyama Y, Maeda K, Doi H, Koyano S, Takeuchi H, Kawamoto M, Kohara N, Ando T, Ieda T, Kita Y, Kokubun N, Tsuboi Y, Katoh K, Kino Y, Katsuno M, Iwasaki Y, Yoshida M, Tanaka F, Suzuki IK, Frith MC, Matsumoto N, Sobue G

    Nature genetics   51 ( 8 )   1215 - 1221   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41588-019-0459-y

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  • RNA sequencing solved the most common but unrecognized NEB pathogenic variant in Japanese nemaline myopathy 査読

    Kohei Hamanaka, Satoko Miyatake, Eriko Koshimizu, Yoshinori Tsurusaki, Satomi Mitsuhashi, Kazuhiro Iwama, Ahmed N. Alkanaq, Atsushi Fujita, Eri Imagawa, Yuri Uchiyama, Nozomu Tawara, Yukio Ando, Yohei Misumi, Mariko Okubo, Mitsuko Nakashima, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Aritoshi Iida, Ichizo Nishino, Naomichi Matsumoto

    Genetics in Medicine   21 ( 7 )   1629 - 1638   2019年7月

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    掲載種別:研究論文(学術雑誌)  

    © 2018, American College of Medical Genetics and Genomics. Purpose: The diagnostic rate for Mendelian diseases by exome sequencing (ES) is typically 20–40%. The low rate is partly because ES misses deep-intronic or synonymous variants leading to aberrant splicing. In this study, we aimed to apply RNA sequencing (RNA-seq) to efficiently detect the aberrant splicings and their related variants. Methods: Aberrant splicing in biopsied muscles from six nemaline myopathy (NM) cases unresolved by ES were analyzed with RNA-seq. Variants related to detected aberrant splicing events were analyzed with Sanger sequencing. Detected variants were screened in NM patients unresolved by ES. Results: We identified a novel deep-intronic NEB pathogenic variant, c.1569+339A>G in one case, and another novel synonymous NEB pathogenic variant, c.24684G>C (p.Ser8228Ser) in three cases. The c.24684G>C variant was observed to be the most frequent among all NEB pathogenic variants in normal Japanese populations with a frequency of 1 in 178 (20 alleles in 3552 individuals), but was previously unrecognized. Expanded screening of the variant identified it in a further four previously unsolved nemaline myopathy cases. Conclusion: These results indicated that RNA-seq may be able to solve a large proportion of previously undiagnosed muscle diseases.

    DOI: 10.1038/s41436-018-0360-6

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  • Single-fiber electromyography-based diagnosis of CACNA1A mutation in children: A potential role of the electrodiagnosis in the era of whole exome sequencing. 査読

    Hirasawa-Inoue A, Ishiyama A, Takeshita E, Shimizu-Motohashi Y, Saito T, Komaki H, Nakagawa E, Yuasa S, Saitsu H, Hamanaka K, Miyatake S, Matsumoto N, Sasaki M

    Brain & development   41 ( 10 )   905 - 909   2019年7月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.braindev.2019.06.006

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  • MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration. 査読 国際誌

    Hamanaka K, Takata A, Uchiyama Y, Miyatake S, Miyake N, Mitsuhashi S, Iwama K, Fujita A, Imagawa E, Alkanaq AN, Koshimizu E, Azuma Y, Nakashima M, Mizuguchi T, Saitsu H, Wada Y, Minami S, Katoh-Fukui Y, Masunaga Y, Fukami M, Hasegawa T, Ogata T, Matsumoto N

    Human molecular genetics   28 ( 14 )   2319 - 2329   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/hmg/ddz066

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  • Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy 国際誌

    Takata Atsushi, Nakashima Mitsuko, Saitsu Hirotomo, Mizuguchi Takeshi, Mitsuhashi Satomi, Takahashi Yukitoshi, Okamoto Nobuhiko, Osaka Hitoshi, Nakamura Kazuyuki, Tohyama Jun, Haginoya Kazuhiro, Takeshita Saoko, Kuki Ichiro, Okanishi Tohru, Goto Tomohide, Sasaki Masayuki, Sakai Yasunari, Miyake Noriko, Miyatake Satoko, Tsuchida Naomi, Iwama Kazuhiro, Minase Gaku, Sekiguchi Futoshi, Fujita Atsushi, Imagawa Eri, Koshimizu Eriko, Uchiyama Yuri, Hamanaka Kohei, Ohba Chihiro, Itai Toshiyuki, Aoi Hiromi, Saida Ken, Sakaguchi Tomohiro, Den Kouhei, Takahashi Rina, Ikeda Hiroko, Yamaguchi Tokito, Tsukamoto Kazuki, Yoshitomi Shinsaku, Oboshi Taikan, Imai Katsumi, Kimizu Tomokazu, Kobayashi Yu, Kubota Masaya, Kashii Hirofumi, Baba Shimpei, Iai Mizue, Kira Ryutaro, Hara Munetsugu, Ohta Masayasu, Miyata Yohane, Miyata Rie, Takanashi Jun-ichi, Matsui Jun, Yokochi Kenji, Shimono Masayuki, Amamoto Masano, Takayama Rumiko, Hirabayashi Shinichi, Aiba Kaori, Matsumoto Hiroshi, Nabatame Shin, Shiihara Takashi, Kato Mitsuhiro, Matsumoto Naomichi

    NATURE COMMUNICATIONS   10 ( 1 )   2506 - 2506   2019年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41467-019-10482-9

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  • L-dopa反応性の眼球運動異常発作を呈し、SPR変異の同定により、セピアプテリン還元酵素欠損症と診断された1例 査読

    中釜 悠, 濱中 耕平, 新宅 治夫, 宮武 聡子, 松本 直通, 久世 崇史, 清水 信隆, 廣畑 晃司, 三牧 正和

    脳と発達   51 ( Suppl. )   S259 - S259   2019年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • Leaky splicing variant in sepiapterin reductase deficiency Are milder cases escaping diagnosis? 査読

    Yu Nakagama, Kohei Hamanaka, Masakazu Mimaki, Haruo Shintaku, Satoko Miyatake, Naomichi Matsumoto, Koji Hirohata, Ryo Inuzuka, Akira Oka

    NEUROLOGY-GENETICS   5 ( 2 )   e319   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Sepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH4) synthesis.(1) Unlike other forms of BH4-deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening. Owing to its variable presenting features and need for a sensitive method of CSF analysis, diagnosis of SRD may be compromised in mild phenotypes.(2)

    DOI: 10.1212/NXG.0000000000000319

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  • SOFT syndrome in a patient from Chile. 査読

    Saida K, Silva S, Solar B, Fujita A, Hamanaka K, Mitsuhashi S, Koshimizu E, Mizuguchi T, Miyatake S, Takata A, Miyake N, Matsumoto N

    Am J Med Genet A.   179 ( 3 )   338 - 340   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 眼球運動失行様所見を伴い小脳性運動失調と鑑別を要したNKX2-1関連疾患の5歳男児例 査読

    小野 博也, 石山 昭彦, 竹下 絵里, 本橋 裕子, 齋藤 貴志, 小牧 宏文, 中川 栄二, 濱中 耕平, 宮武 聡子, 松本 直通, 佐々木 征行

    脳と発達   51 ( 2 )   125 - 125   2019年3月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic. 査読 国際誌

    Kohei Hamanaka, Satoko Miyatake, Ayelet Zerem, Dorit Lev, Luba Blumkin, Kenji Yokochi, Atsushi Fujita, Eri Imagawa, Kazuhiro Iwama, Mitsuko Nakashima, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Marjo S van der Knaap, Tally Lerman-Sagie, Naomichi Matsumoto

    Journal of human genetics   63 ( 12 )   1223 - 1229   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated. In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy. In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.

    DOI: 10.1038/s10038-018-0516-x

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  • A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia. 査読 国際誌

    Uchiyama Y, Yanagisawa K, Kunishima S, Shiina M, Ogawa Y, Nakashima M, Hirato J, Imagawa E, Fujita A, Hamanaka K, Miyatake S, Mitsuhashi S, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N, Mizuguchi T

    Clinical genetics   94 ( 6 )   548 - 553   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cge.13423

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  • De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies. 査読 国際誌

    Hamanaka K, Sugawara Y, Shimoji T, Nordtveit TI, Kato M, Nakashima M, Saitsu H, Suzuki T, Yamakawa K, Aukrust I, Houge G, Mitsuhashi S, Takata A, Iwama K, Alkanaq A, Fujita A, Imagawa E, Mizuguchi T, Miyake N, Miyatake S, Matsumoto N

    European journal of human genetics : EJHG   27 ( 3 )   378 - 383   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41431-018-0289-x

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  • 当院で経験したGNAO1遺伝子変異の3症例 幅広いスペクトラムを有するG蛋白の異常

    西田 裕哉, 熊田 聡子, 白井 育子, 濱中 耕平, 宮武 聡子, 栗原 まな, 島田 姿野, 眞下 秀明, 宮田 世羽, 栗原 栄二, 松本 直通

    脳と発達   50 ( 5 )   371 - 372   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • Confirmation of SLC5A7-related distal hereditary motor neuropathy 7 in a family outside Wales. 査読 国際誌

    K Hamanaka, K Takahashi, S Miyatake, S Mitsuhashi, H Hamanoue, Y Miyaji, R Fukai, H Doi, A Fujita, E Imagawa, K Iwama, M Nakashima, T Mizuguchi, A Takata, N Miyake, H Takeuchi, F Tanaka, N Matsumoto

    Clinical genetics   94 ( 2 )   274 - 275   2018年8月

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    記述言語:英語  

    DOI: 10.1111/cge.13369

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  • A novel missense SNAP25b mutation in two affected siblings from an Israeli family showing seizures and cerebellar ataxia. 査読 国際誌

    Hiroyuki Fukuda, Eri Imagawa, Kohei Hamanaka, Atsushi Fujita, Satomi Mitsuhashi, Satoko Miyatake, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Uri Kramer, Naomichi Matsumoto, Aviva Fattal-Valevski

    Journal of human genetics   63 ( 5 )   673 - 676   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SNAP25 is a core component of the soluble N-ethylmaleimide-sensitive factor attachment receptor complex, which plays a critical role in synaptic vesicle exocytosis. To date, six de novo SNAP25 mutations have been reported in patients with neurological features including seizures, intellectual disability, severe speech delay, and cerebellar ataxia. Here, we analyzed an Israeli family with two affected siblings showing seizures and cerebellar dysfunction by whole-exome sequencing, and identified a novel missense SNAP25 mutation (c.176G > C, p.Arg59Pro) inherited from their unaffected father. Two SNAP25 isoforms are known, SNAP25a and SNAP25b, which each contain a different exon 5. The c.176G > C mutation found in this study was specific to SNAP25b, while five previously reported mutations were identified in exons common to both isoforms. Another was previously reported to be specific to SNAP25b. Comparing clinical features of reported patients with SNAP25 mutations, the current patients demonstrated apparently milder clinical features with normal intelligence, and no magnetic resonance imaging abnormality or facial dysmorphism. Our results expand the clinical spectrum of SNAP25 mutations.

    DOI: 10.1038/s10038-018-0421-3

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  • KMT2B遺伝子変異2例に対する淡蒼球内節刺激療法 定量的運動機能解析システムを用いた検討 査読

    宮田 世羽, 吉田 大峰, 本多 武尊, 熊田 聡子, 眞下 秀明, 西田 裕哉, 白井 育子, 横地 房子, 筧 慎治, 濱中 耕平, 宮武 聡子, 松本 直通, 服部 文子, 瓦井 俊孝, 谷口 真

    脳と発達   50 ( Suppl. )   S304 - S304   2018年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • A 62-Year-Old Woman with A History of Muscle Pain and Skin Rash for 1 Month. 査読 国際誌

    Jantima Tanboon, Akinori Uruha, Kohei Hamanaka, Juri Hasegawa, Ichizo Nishino

    Brain pathology (Zurich, Switzerland)   28 ( 1 )   121 - 122   2018年1月

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    記述言語:英語  

    DOI: 10.1111/bpa.12574

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  • Aberrant Myokine Signaling in Congenital Myotonic Dystrophy 査読

    Masayuki Nakamori, Kohei Hamanaka, James D. Thomas, Eric T. Wang, Yukiko K. Hayashi, Masanori P. Takahashi, Maurice S. Swanson, Ichizo Nishino, Hideki Mochizuki

    CELL REPORTS   21 ( 5 )   1240 - 1252   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Myotonic dystrophy types 1 (DM1) and 2 (DM2) are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM), a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6) myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling.

    DOI: 10.1016/j.celrep.2017.10.018

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  • Skeletal Muscle Involvement in Antisynthetase Syndrome 査読

    Eri Noguchi, Akinori Uruha, Shigeaki Suzuki, Kohei Hamanaka, Yuko Ohnuki, Jun Tsugawa, Yurika Watanabe, Jin Nakahara, Takashi Shiina, Norihiro Suzuki, Ichizo Nishino

    JAMA NEUROLOGY   74 ( 8 )   992 - 999   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    IMPORTANCE Antisynthetase syndrome, characterized bymyositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients' serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies.OBJECTIVE To elucidate the clinical features of myositis in patients with antisynthetase syndrome.DESIGN, SETTING, AND PARTICIPANTS In this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016.EXPOSURES Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped.MAIN OUTCOMES AND MEASURES The main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied.RESULTS Of 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1-the anti-OJ antibody-was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis.CONCLUSIONS AND RELEVANCE Although clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.

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  • 【最新遺伝医学研究と遺伝カウンセリング シリーズ2 最新精神・神経遺伝医学研究と遺伝カウンセリング】(第2章)精神・神経疾患の遺伝医学研究・診療各論 筋疾患の遺伝医学研究 査読

    濱中 耕平, 西野 一三

    遺伝子医学MOOK   別冊 ( 最新精神・神経遺伝医学研究と遺伝カウンセリング )   164 - 167   2017年4月

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    記述言語:日本語   出版者・発行元:(株)メディカルドゥ  

    遺伝性筋疾患を取り巻く状況は大きく変わりつつある。従来,遺伝性筋疾患に治療法はなく,診断の意義は必ずしも大きくなかった。昨今,遺伝性筋疾患に対する多くの治療法が考案されはじめた。そういった治療法の多くは,原因遺伝子特異的,時には原因遺伝子変異特異的なものである。それ故,遺伝子変異の同定が重要となりつつある。こういった遺伝子診断の重要性が増していることを踏まえ,最新の遺伝医学研究におけるトピックスを総覧したい。(著者抄録)

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  • Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies 査読

    Wen-Chen Liang, Akinori Uruha, Shigeaki Suzuki, Nobuyuki Murakami, Eri Takeshita, Wan-Zi Chen, Yuh-Jyh Jong, Yukari Endo, Hirofumi Komaki, Tatsuya Fujii, Yutaka Kawano, Madoka Mori-Yoshimura, Yasushi Oya, Jianying Xi, Wenhua Zhu, Chongbo Zhao, Yurika Watanabe, Keisuke Ikemoto, Atsuko Nishikawa, Kohei Hamanaka, Satomi Mitsuhashi, Norihiro Suzuki, Ichizo Nishino

    RHEUMATOLOGY   56 ( 2 )   287 - 293   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Objective. Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies.Methods. We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies.Results. We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled.Conclusion. Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

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  • Sarcoplasmic MxA expression A valuable marker of dermatomyositis 査読

    Akinori Uruha, Atsuko Nishikawa, Rie S. Tsuburaya, Kohei Hamanaka, Masataka Kuwana, Yurika Watanabe, Shigeaki Suzuki, Norihiro Suzuki, Ichizo Nishino

    NEUROLOGY   88 ( 5 )   493 - 500   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM).Methods: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti-tRNA-synthetase antibody-associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries.Results: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population.Conclusions: Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. Classification of evidence: This study provides Class II evidence that immunohistochemistrydetected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.

    DOI: 10.1212/WNL.0000000000003568

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  • 顔面肩甲上腕型筋ジストロフィー2型(FSHD2)と遺伝子診断した1例 査読

    徳岡 秀紀, 上田 健博, 遠藤 浩信, 立花 久嗣, 千原 典夫, 関口 兼司, 古和 久朋, 苅田 典生, 濱中 耕平, 西野 一三, 戸田 達史

    臨床神経学   56 ( 11 )   795 - 795   2016年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • HLA-DRB1 ALLELES IN IMMUNE-MEDIATED NECROTIZING MYOPATHY 査読

    Yuko Ohnuki, Shigeaki Suzuki, Takashi Shiina, Akinori Uruha, Yurika Watanabe, Shingo Suzuki, Shunichiro Izumi, Jin Nakahara, Kohei Hamanaka, Kazuko Takayama, Norihiro Suzuki, Ichizo Nishino

    NEUROLOGY   87 ( 18 )   1954 - 1955   2016年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1212/WNL.0000000000003160

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  • 壊死性ミオパチーにおける免疫治療と神経学的予後 抗SRP抗体と抗HMGCR抗体の比較 査読

    渡邊 由里香, 鈴木 重明, 漆葉 章典, 濱中 耕平, 中原 仁, 高山 和子, 鈴木 則宏, 西野 一三

    神経治療学   33 ( 5 )   S225 - S225   2016年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経治療学会  

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  • Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy 査読

    Yurika Watanabe, Akinori Uruha, Shigeaki Suzuki, Jin Nakahara, Kohei Hamanaka, Kazuko Takayama, Norihiro Suzuki, Ichizo Nishino

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   87 ( 10 )   1038 - 1044   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Objective To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR).Methods We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively.Results Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups.Conclusions Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti-HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics.

    DOI: 10.1136/jnnp-2016-313166

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  • "Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations" (vol 26, pg 300, 2016) 査読

    Kohei Hamanaka, Kanako Goto, Mami Arai, Koji Nagao, Chikashi Obuse, Satoru Noguchi, Yukiko K. Hayashi, Satomi Mitsuhashi, Ichizo Nishino

    NEUROMUSCULAR DISORDERS   26 ( 7 )   472 - 472   2016年7月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2016.05.015

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  • Corrigendum to "Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations": [Neuromuscular Disorders 26/4-5 (2016) 300-308]. 査読 国際誌

    Kohei Hamanaka, Kanako Goto, Mami Arai, Koji Nagao, Chikashi Obuse, Satoru Noguchi, Yukiko K Hayashi, Satomi Mitsuhashi, Ichizo Nishino

    Neuromuscular disorders : NMD   26 ( 7 )   472 - 472   2016年7月

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  • Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations 査読

    Kohei Hamanaka, Kanako Goto, Mami Arai, Koji Nagao, Chikashi Obuse, Satoru Noguchi, Yukiko K. Hayashi, Satomi Mitsuhashi, Ichizo Nishino

    NEUROMUSCULAR DISORDERS   26 ( 4-5 )   300 - 308   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a genetic muscular disorder characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array, D4Z4. FSHD2 is caused by heterozygous mutations in the gene encoding structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1). Because there has been no study on FSHD2 in Asian populations, it is not known whether this disease mechanism is widely seen. To identify FSHD2 patients with SMCHD1 mutations in the Japanese population, bisulfite pyrosequencing was used to measure DNA methylation on the D4Z4 repeat array, and in patients with DNA hypomethylation, the SMCHD1 gene was sequenced by the Sanger method. Twenty patients with D4Z4 hypomethylation were identified. Of these, 13 patients from 11 unrelated families had ten novel and one reported SMCHD4 mutations: four splice-site, two nonsense, two in-frame deletion, two out-of-frame deletion, and one missense mutations. One of the splice-site mutations was homozygous in the single patient identified with this. In summary, we identified novel SMCHD1 mutations in a Japanese cohort of FSHD2 patients, confirming the presence of this disease in a wider population than previously known. (C) 2016 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.nmd.2016.03.001

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  • Muscle from a 20-week-old myotubular myopathy fetus is not myotubular 査読

    Kohei Hamanaka, Ikuhiro Inami, Takahito Wada, Satomi Mitsuhashi, Satoru Noguchi, Yukiko K. Hayashi, Ichizo Nishino

    NEUROMUSCULAR DISORDERS   26 ( 3 )   234 - 235   2016年3月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2015.11.010

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  • 顔面肩甲上腕型筋ジストロフィーの遺伝学的解析2015 査読

    後藤 加奈子, 三橋 里美, 濱中 耕平, 西野 一三

    臨床神経学   55 ( Suppl. )   S388 - S388   2015年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 顔面肩甲上腕型筋ジストロフィー患者のエピゲノム解析 査読

    三橋 里美, 濱中 耕平, 後藤 加奈子, 西野 一三

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P1298] - [2P1298]   2015年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • 先天性筋強直性ジストロフィー症の筋未熟性とCpGメチル化異常 査読

    中森 雅之, 濱中 耕平, 林 由起子, 西野 一三, 高橋 正紀, 望月 秀樹

    臨床神経学   55 ( Suppl. )   S387 - S387   2015年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 【骨格筋症候群(第2版)-その他の神経筋疾患を含めて-下】ミトコンドリア病 ミトコンドリア病の臨床的表現型による分類 Myopathy,lactic acidosis,and sideroblastic anemia(MLASA) 査読

    濱中 耕平, 西野 一三

    日本臨床   別冊 ( 骨格筋症候群(下) )   243 - 245   2015年7月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • Useful differential diagnostic markers between congenital myotonic dystrophy and X-linked myotubular myopathy 査読

    Hamanaka K, Noguchi S, Hayashi Y. K, Nishino I

    NEUROMUSCULAR DISORDERS   23 ( 9-10 )   761   2013年10月

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MISC

  • 肢帯型筋ジストロフィー2型(LGMD2A)の24歳女性例の長期経過

    阪下達哉, 阪下達哉, 中村勝哉, 中村勝哉, 中村勝哉, 石川真澄, 石川真澄, 平林伸一, 酒井典子, 濱中耕平, 宮武聡子, 松本直通, 古庄知己, 古庄知己

    日本遺伝カウンセリング学会誌   42 ( 2 )   2021年

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  • セピアプテリン還元酵素欠損症に認められたleaky splicing variant

    中釜悠, 中釜悠, 三牧正和, 新宅治夫, 濱中耕平, 宮武聡子, 松本直通, 犬塚亮, 岡明

    日本小児遺伝学会学術集会プログラム・抄録集   41st   2019年

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  • 発作性の運動障害を認めたKIAA2022遺伝子異常の女性例

    小笠原 真志, 中川 栄二, 濱中 耕平, 竹下 絵里, 本橋 裕子, 石山 昭彦, 斎藤 貴志, 小牧 宏文, 須貝 研司, 宮武 聡子, 松本 直通, 佐々木 征行

    脳と発達   50 ( 5 )   370 - 370   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • KMT2B遺伝子変異2例に対する淡蒼球内節刺激療法 定量的運動機能解析システムを用いた検討

    宮田 世羽, 吉田 大峰, 本多 武尊, 熊田 聡子, 眞下 秀明, 西田 裕哉, 白井 育子, 横地 房子, 筧 慎治, 濱中 耕平, 宮武 聡子, 松本 直通, 服部 文子, 瓦井 俊孝, 谷口 真

    脳と発達   50 ( Suppl. )   S304 - S304   2018年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • 大脳白質形成不全症の新規遺伝子TUBB4A 招待

    濱中 耕平, 宮武 聡子

    神経内科   88 ( 2 )   2018年2月

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    記述言語:日本語  

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  • Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl coenzyme a reductase antibodies

    W. Liang, A. Uruha, S. Suzuki, H. Komaki, W. Zhu, Y. Watanabe, A. Nishikawa, K. Hamanaka, S. Mitsuhashi, I. Nishino

    NEUROMUSCULAR DISORDERS   26   S143 - S144   2016年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2016.06.210

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  • 筋病理診断を施行したanti-synthetase syndromeの臨床特徴

    野口 恵里, 鈴木 重明, 漆葉 章典, 大貫 優子, 濱中 耕平, 渡邊 由里香, 中原 仁, 椎名 隆, 鈴木 則宏, 西野 一三

    神経免疫学   21 ( 1 )   174 - 174   2016年9月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 筋強直性ジストロフィーの分子病態と治療法に関する研究

    高橋正紀, 中森雅之, 木村卓, 濱中耕平, 穀内洋介, 古田充, 藤村晴俊, 佐古田三郎, 望月秀樹, 林由起子, 林由起子, SWANSON Maurice S., THORNTON Charles A., CHARLET-BERGUERAND Nicolas, 西野一三

    筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 平成23-25年度 総括研究報告書   2014年

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受賞

  • 奨励賞

    2022年11月   日本人類遺伝学会  

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共同研究・競争的資金等の研究課題

  • スプライシング関連タンデムリピートが遺伝性疾患の病態に果たす役割の解明

    研究課題/領域番号:22K15646  2022年4月 - 2024年3月

    日本学術振興会  科学研究費助成事業  若手研究

    浜中 耕平

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    配分額:3510000円 ( 直接経費:2700000円 、 間接経費:810000円 )

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  • クリッペルフェイル症候群の原因遺伝子の解明

    研究課題/領域番号:20K16932  2020年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業  若手研究

    浜中 耕平

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    配分額:3510000円 ( 直接経費:2700000円 、 間接経費:810000円 )

    染色体5番と8番の転座によるクリッペルフェイル症候群と小頭症のメカニズムの解明を試みた。この二つの症状は、骨芽細胞の骨化の異常と解釈できるため、この観点から解析した。まず、全ゲノム解析により、本転座の断端を決定した。この断端が破壊する2つのトポロジカルドメイン内に、骨芽細胞の骨化を促進するFGF18が位置していた。FGF18が転座により位置するトポロジカルドメイン内に、エンハンサーが密集した領域を同定した。次に、DNA配列から遺伝子の転写量を予測する深層学習モデル(インシリコルシフェラーゼアッセイと名付けた)で、このエンハンサー群がFGF18の発現量を骨芽細胞で増加させると予測された。

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