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タイトル: | Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss. |
著者: | Ueyama, Takehiko Ninoyu, Yuzuru Nishio, Shin-Ya Miyoshi, Takushi Torii, Hiroko Nishimura, Koji https://orcid.org/0000-0003-0507-8184 (unconfirmed) Sugahara, Kazuma Sakata, Hideaki Thumkeo, Dean Sakaguchi, Hirofumi Watanabe, Naoki https://orcid.org/0000-0001-8492-200X (unconfirmed) Usami, Shin-Ichi Saito, Naoaki Kitajiri, Shin-Ichiro |
著者名の別形: | 上山, 健彦 北尻, 真一郎 |
キーワード: | actin deafness DIAPH1 DFNA1 stereocilia |
発行日: | 5-Oct-2016 |
出版者: | John Wiley & Sons, Ltd |
誌名: | EMBO molecular medicine |
巻: | 8 |
号: | 11 |
開始ページ: | 1310 |
終了ページ: | 1324 |
論文番号: | e201606609 |
抄録: | DIAPH1 encodes human DIA1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH1 mutation causes autosomal dominant nonsyndromic sensorineural hearing loss, DFNA1, characterized by progressive deafness starting in childhood. The mutation occurs near the C-terminus of the diaphanous autoregulatory domain (DAD) of DIA1, which interacts with its N-terminal diaphanous inhibitory domain (DID), and may engender constitutive activation of DIA1. However, the underlying pathogenesis that causes DFNA1 is unclear. We describe a novel patient-derived DIAPH1 mutation (c.3610C>T) in two unrelated families, which results in early termination prior to a basic amino acid motif (RRKR [1204-1207]) at the DAD C-terminus. The mutant DIA1 (R1204X) disrupted the autoinhibitory DID-DAD interaction and was constitutively active. This unscheduled activity caused increased rates of directional actin polymerization movement and induced formation of elongated microvilli. Mice expressing FLAG-tagged DIA1 (R1204X) experienced progressive deafness and hair cell loss at the basal turn and had various morphological abnormalities in stereocilia (short, fused, elongated, sparse). Thus, the basic region of the DAD mediates DIA1 autoinhibition; disruption of the DID-DAD interaction and consequent activation of DIA1 (R1204X) causes DFNA1. |
記述: | 遺伝性感音難聴の原因遺伝子変異を同定し 難聴患者の病態を再現した遺伝子操作マウスの作製に成功. 京都大学プレスリリース. 2016-10-11. |
著作権等: | © 2016 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
URI: | http://hdl.handle.net/2433/216929 |
DOI(出版社版): | 10.15252/emmm.201606609 |
PubMed ID: | 27707755 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2016-10-11 |
出現コレクション: | 学術雑誌掲載論文等 |
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