Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64

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• 作者：Jing Cheng¹ ; ¹⁰ ; Yuhua Zhu¹ ; ¹⁰ ; Sudan He² ; ³ ; Yanping Lu⁴ ; Jing Chen¹ ; Bing Han¹ ; Marco Petrillo⁵ ; Kazimierz  ; O. Wrzeszczynski⁶ ; Shiming Yang¹ ; Pu Dai¹ ; Suoqiang Zhai¹ ; Dongyi Han¹ ; Michael  ; Q. Zhang⁶ ; Wei Li⁷ ; Xuezhong Liu⁸ ; Huawei Li⁹ ; Zheng-Yi Chen⁵ ; Huijun Yuan¹ ; ^{yuanhj301@yahoo.com.cn"" rel=""nofollow}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：15 July 2011
• 年：2011
• 卷：89
• 期：1
• 页码：56-66
• 全文大小：1767 K

文摘

SMAC/DIABLO is a mitochondrial proapoptotic protein that is released from mitochondria during apoptosis and counters the inhibitory activities of inhibitor of apoptosis proteins, IAPs. By linkage analysis and candidate screening, we identified a heterozygous SMAC/DIABLO mutation, c.377C>T (p.Ser126Leu, refers to p.Ser71Leu in the mature protein) in a six-generation Chinese kindred characterized by dominant progressive nonsyndromic hearing loss, designated as DFNA64. SMAC/DIABLO is highly expressed in human embryonic ears and is enriched in the developing mouse inner-ear hair cells, suggesting it has a role in the development and homeostasis of hair cells. We used a functional study to demonstrate that the SMAC/DIABLO^S71L mutant, while retaining the proapoptotic function, triggers significant degradation of both wild-type and mutant SMAC/DIABLO and renders host mitochondria susceptible to calcium-induced loss of the membrane potential. Our work identifies DFNA64 as the human genetic disorder associated with SMAC/DIABLO malfunction and suggests that mutant SMAC/DIABLO^S71L might cause mitochondrial dysfunction.