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

Cheng, J., Zhu, Y., He, S., Lu, Y., Chen, J., Han, B., Petrillo, M., Wrzeszczynski, K. O., Yang, S., Dai, P., Zhai, S., Han, D., Zhang, M. Q., Li, W., Liu, X., Li, H., Chen, Z. Y., Yuan, H. (July 2011) Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64. The American Journal of Human Genetics, 89 (1). pp. 56-66. ISSN 0002-9297

URL: https://www.ncbi.nlm.nih.gov/pubmed/21722859
DOI: 10.1016/j.ajhg.2011.05.027

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.

Item Type: Paper
Uncontrolled Keywords: second mitochondrial activator of caspase adul aged animal experiment animal tissue autosomal dominant disorder Chinese clinical article disorders of mitochondrial functions embryo female hearing loss human linkage analysis male missense mutation mitochondrial membrane potential mouse nucleotide sequence protein degradation
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organism description > animal behavior > auditory
organism description > animal behavior > auditory > hearing
organism description > animal > mammal > primates > hominids > human
organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria
CSHL Authors:
Communities: CSHL labs > Zhang lab
Depositing User: CSHL Librarian
Date: 15 July 2011
Date Deposited: 07 Nov 2011 21:49
Last Modified: 26 Feb 2018 17:47
PMCID: PMC3135809
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15616

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving