title: Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.
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.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3705, USA. rinaldic@ninds.nih.gov
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Christopher
authors.initials: C
authors.lastname: Grunseich
authors.forename: Irina F
authors.initials: IF
authors.lastname: Sevrioukova
authors.forename: Alice
authors.initials: A
authors.lastname: Schindler
authors.forename: Iren
authors.initials: I
authors.lastname: Horkayne-Szakaly
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Guida
authors.initials: G
authors.lastname: Landouré
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
authors.forename: Carsten
authors.initials: C
authors.lastname: Bönnemann
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D059906:Neuroimaging; D010084:Oxidation-Reduction; D010375:Pedigree; D011487:Protein Conformation; D021381:Protein Transport
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor