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ササキ リヨウ
Sasaki Riyou
佐々木 亮 所属 医学部 医学科（東京女子医科大学病院） 職種 講師 |
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| 論文種別 | 原著 |
| 言語種別 | 英語 |
| 査読の有無 | 査読あり |
| 表題 | Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation. |
| 掲載誌名 | 正式名：Journal of the American College of Cardiology 略 称：J Am Coll Cardiol ISSNコード：07351097/15583597 |
| 掲載区分 | 国外 |
| 出版社 | Elsevier |
| 巻・号・頁 | 70(3),pp.358-370 |
| 著者・共著者 | SEKI Akiko†, ISHIKAWA Taisuke, DAUMY Xavier, MISHIMA Hiroyuki, BARC Julien, SASAKI Ryo, NISHII Kiyomasa, SAITO Kayoko, URANO Mari, OHNO Seiko, OTSUKI Saki, KIMOTO Hiroki, BARUTEAU Alban-Elouen, THOLLET Aurelie, FOUCHARD Swanny, BONNAUD Stéphanie, PARENT Philippe, SHIBATA Yosaburo, PERRIN Jean-Philippe, LE Marec Hervé, HAGIWARA Nobuhisa, MERCIER Sandra, HORIE Minoru, PROBST Vincent, YOSHIURA Koh-Ichiro, REDON Richard, SCHOTT Jean-Jacques, MAKITA Naomasa |
| 発行年月 | 2017/07 |
| 概要 | BACKGROUND:
Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic f OBJECTIVES: The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation. METHODS: The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice. RESULTS: The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance. CONCLUSIONS: Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation. |
| DOI | 10.1016/j.jacc.2017.05.039 |
| PMID | 28705318 |