Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64 |
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| Authors: | Cheng Jing Zhu Yuhua He Sudan Lu Yanping Chen Jing Han Bing Petrillo Marco Wrzeszczynski Kazimierz O Yang Shiming Dai Pu Zhai Suoqiang Han Dongyi Zhang Michael Q Li Wei Liu Xuezhong Li Huawei Chen Zheng-Yi Yuan Huijun |
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| Affiliation: | 1Institute of Otolaryngology, Chinese PLA General Hospital, Beijing 100853, China;2National Institute of Biological Sciences, No.7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China;3Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou 215325, China;4Department of Obstetrics and Gynecology, Chinese People's Liberation Army General Hospital, Beijing 100853, China;5Eaton-Peabody Laboratory, Department of Otolaryngology, The Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA;6Michael Zhang Lab, Koch 2124, Computational Biology and Bioinformatics, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA;7Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;8Department of Otolaryngology, University of Miami, Miami, FL 33136, USA;9Department of Otology & Skull Base Surgery, Affiliated Eye and Otolaryngology Hospital of Fudan University, 83 Fenyang Road, Shanghai 200031, China |
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| 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/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. |
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