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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1095-1102
Number of pages8
JournalAmerican Journal of Human Genetics
Volume91
Issue number6
DOIs
Publication statusPublished - Dec 7 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landouré, G., Kennerson, M. L., Burnett, B. G., Bönnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., & Fischbeck, K. H. (2012). Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. American Journal of Human Genetics, 91(6), 1095-1102. https://doi.org/10.1016/j.ajhg.2012.10.008