期刊
EUROPEAN HEART JOURNAL
卷 34, 期 3, 页码 201-210出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehs373
关键词
Sudden cardiac death; Arrhythmia; Cardiomyopathy; Cell adhesion molecules; Genetics
资金
- Research Foundation - Flanders (FWO)
- Concerted Research Actions - Ghent University (GOA)
- TELETHON, Rome [GGP09293]
- Fondazione CARIPARO, Padua
- AFM, Paris [14776]
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that T-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cellcell adhesion in contractile cardiomyocytes. We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands. They are located in important domains of T-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and -catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据