Document Detail

Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.
MedLine Citation:
PMID:  23217327     Owner:  NLM     Status:  MEDLINE    
Cowchock syndrome (CMTX4) is a slowly progressive X-linked recessive disorder with axonal neuropathy, deafness, and cognitive impairment. The disease locus was previously mapped to an 11 cM region at chromosome X: q24-q26. Exome sequencing of an affected individual from the originally described family identified a missense change c.1478A>T (p.Glu493Val) in AIFM1, the gene encoding apoptosis-inducing factor (AIF) mitochondrion-associated 1. The change is at a highly conserved residue and cosegregated with the phenotype in the family. AIF is an FAD-dependent NADH oxidase that is imported into mitochondria. With apoptotic insults, a N-terminal transmembrane linker is cleaved off, producing a soluble fragment that is released into the cytosol and then transported into the nucleus, where it triggers caspase-independent apoptosis. Another AIFM1 mutation that predicts p.Arg201del has recently been associated with severe mitochondrial encephalomyopathy in two infants by impairing oxidative phosphorylation. The c.1478A>T (p.Glu493Val) mutation found in the family reported here alters the redox properties of the AIF protein and results in increased cell death via apoptosis, without affecting the activity of the respiratory chain complexes. Our findings expand the spectrum of AIF-related disease and provide insight into the effects of AIFM1 mutations.
Carlo Rinaldi; Christopher Grunseich; Irina F Sevrioukova; Alice Schindler; Iren Horkayne-Szakaly; Costanza Lamperti; Guida Landouré; Marina L Kennerson; Barrington G Burnett; Carsten Bönnemann; Leslie G Biesecker; Daniele Ghezzi; Massimo Zeviani; Kenneth H Fischbeck
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  91     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-10     Completed Date:  2013-02-14     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1095-102     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Apoptosis / genetics
Apoptosis Inducing Factor / chemistry,  genetics*,  metabolism
Base Sequence
Brain / pathology
Cell Nucleus / genetics,  metabolism
Charcot-Marie-Tooth Disease / diagnosis,  genetics*,  metabolism
Hearing Loss, Sensorineural / diagnosis,  genetics*,  metabolism
Magnetic Resonance Imaging
Mental Retardation, X-Linked / diagnosis,  genetics*,  metabolism
Mitochondria / genetics,  metabolism,  ultrastructure
Models, Molecular
Muscle, Skeletal / metabolism,  pathology,  ultrastructure
Protein Conformation
Protein Transport
Grant Support
GGP11011//Telethon; GM67637/GM/NIGMS NIH HHS; GPP10005//Telethon
Reg. No./Substance:
0/AIFM1 protein, human; 0/Apoptosis Inducing Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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