title: Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64.
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.
authors: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors: Jing
authors: J
authors: Cheng
authors: Yuhua
authors: Y
authors: Zhu
authors: Sudan
authors: S
authors: He
authors: Yanping
authors: Y
authors: Lu
authors: Jing
authors: J
authors: Chen
authors: Bing
authors: B
authors: Han
authors: Marco
authors: M
authors: Petrillo
authors: Kazimierz O
authors: KO
authors: Wrzeszczynski
authors: Shiming
authors: S
authors: Yang
authors: Pu
authors: P
authors: Dai
authors: Suoqiang
authors: S
authors: Zhai
authors: Dongyi
authors: D
authors: Han
authors: Michael Q
authors: MQ
authors: Zhang
authors: Wei
authors: W
authors: Li
authors: Xuezhong
authors: X
authors: Liu
authors: Huawei
authors: H
authors: Li
authors: Zheng-Yi
authors: ZY
authors: Chen
authors: Huijun
authors: H
authors: Yuan
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D044466:Asian People; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D006367:HeLa Cells; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering