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.

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

“…16 Over the last few years, many studies have shown the value of exome sequencing for gene discovery purposes in neurological disorders. [19][20][21][22][23] Next-generation sequencing technologies have also accelerated gene discovery in patients with dHMN, 9,24 CMT 25,26 or other inherited neuropathies. [27][28][29] More recently, the use of exome sequencing for diagnostic purposes in genetic disorders with a high degree of genetic heterogeneity such as CMT is being explored.…”

Next-generation sequencing in X-linked intellectual disability

“…References for all genes are in Supplementary Table S1 of the review by Lubs et al, 3 except for SYP, ZNF711, AIFM1, ZMYM3, KDM6A and WDR45. [13][14][15][16][17][18] …”

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

“…While full knockout of AIF or 312 CHCHD4 are embryonic lethal [40,115], distinct AIF point mutations induce an array of 313 human diseases ranging from severe X-linked mitochondrial encephalomyopathy, Cowchock 314 syndrome (X-linked Charcot-Marie-Tooth disease with axonal sensorimotor neuropathy, 315 deafness and cognitive impairment) to infantile motor neuron disease or auditory neuropathy 316 spectrum disorder [116][117][118][119]. The fact that at least one of these pathogenic AIF mutations 317 (G308E, which gives rise to a severe phenotype) reduces AIF binding to CHCHD4 [40], 318 underscores the physiological importance of the AIF-CHCHD4 interaction.…”