Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64

Jing Cheng, Yuhua Zhu, Sudan He, Yanping Lu, Jing Chen, Bing Han, Marco Petrillo, Kazimierz O. Wrzeszczynski, Shiming Yang, Pu Dai, Suoqiang Zhai, Dongyi Han, Michael Q. Zhang, Wei Li, Xuezhong Liu, Huawei Li, Zheng Yi Chen, Huijun Yuan

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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/DIABLOS71L 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/DIABLOS71L might cause mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)56-66
Number of pages11
JournalAmerican journal of human genetics
Volume89
Issue number1
DOIs
StatePublished - Jul 15 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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