Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.

TitleCowchock syndrome is associated with a mutation in apoptosis-inducing factor.
Publication TypeJournal Article
Year of Publication2012
AuthorsRinaldi, C, Grunseich, C, Sevrioukova, IF, Schindler, A, Horkayne-Szakaly, I, Lamperti, C, Landouré, G, Kennerson, ML, Burnett, BG, Bönnemann, C, Biesecker, LG, Ghezzi, D, Zeviani, M, Fischbeck, KH
JournalAm J Hum Genet
Date Published2012 Dec 07
KeywordsApoptosis, Apoptosis Inducing Factor, Base Sequence, Brain, Cell Nucleus, Charcot-Marie-Tooth Disease, Exons, Hearing Loss, Sensorineural, Humans, Magnetic Resonance Imaging, Male, Mental Retardation, X-Linked, Mitochondria, Models, Molecular, Muscle, Skeletal, Mutation, Neuroimaging, Oxidation-Reduction, Pedigree, Protein Conformation, Protein Transport

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.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2012.10.008
PubMed ID23217327
PubMed Central IDPMC3516602
Grant ListGGP11011 / / Telethon / Italy
GPP10005 / / Telethon / Italy
R01 GM067637 / GM / NIGMS NIH HHS / United States
GM67637 / GM / NIGMS NIH HHS / United States