ナカムラ　フミオ   Fumio Nakamura   中村　史雄    所属   医学部 医学科    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy.
掲載誌名	正式名：American journal of human genetics 略　 称：Am J Hum Genet ISSNコード：15376605/00029297
掲載区分	国外
巻・号・頁	106(4),pp.549-558
著者・共著者	Hamanaka Kohei, Imagawa Eri, Koshimizu Eriko, Miyatake Satoko, Tohyama Jun, Yamagata Takanori, Miyauchi Akihiko, Ekhilevitch Nina, Nakamura Fumio, Kawashima Takeshi, Goshima Yoshio, Mohamed Ahmad Rithauddin, Ch'ng Gaik-Siew, Fujita Atsushi, Azuma Yoshiteru, Yasuda Ken, Imamura Shintaro, Nakashima Mitsuko, Saitsu Hirotomo, Mitsuhashi Satomi, Mizuguchi Takeshi, Takata Atsushi, Miyake Noriko, Matsumoto Naomichi
発行年月	2020/04
概要	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
PMID	32169168