title: A frameshift mutation in GRXCR2 causes recessively inherited hearing loss.
abstract: More than 360 million humans are affected with some degree of hearing loss, either early or later in life. A genetic cause for the disorder is present in a majority of the cases. We mapped a locus (DFNB101) for hearing loss in humans to chromosome 5q in a consanguineous Pakistani family. Exome sequencing revealed an insertion mutation in GRXCR2 as the cause of moderate-to-severe and likely progressive hearing loss in the affected individuals of the family. The frameshift mutation is predicted to affect a conserved, cysteine-rich region of GRXCR2, and to result in an abnormal extension of the C-terminus. Functional studies by cell transfections demonstrated that the mutant protein is unstable and mislocalized relative to wild-type GRXCR2, consistent with a loss-of-function mutation. Targeted disruption of Grxcr2 is concurrently reported to cause hearing loss in mice. The structural abnormalities in this animal model suggest a role for GRXCR2 in the development of stereocilia bundles, specialized structures on the apical surface of sensory cells in the cochlea that are critical for sound detection. Our results indicate that GRXCR2 should be considered in differential genetic diagnosis for individuals with early onset, moderate-to-severe and progressive hearing loss.
authors.affiliation: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Imtiaz
authors.forename: David C
authors.initials: DC
authors.lastname: Kohrman
authors.forename: Sadaf
authors.initials: S
authors.lastname: Naz
mesh_terms: D000818:Animals; D059472:Exome; D016368:Frameshift Mutation; D005808:Genes, Recessive; D054477:Glutaredoxins / Q000235:genetics*; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D010375:Pedigree
chemical_list: C000593489:GRXCR2 protein, human; D054477:Glutaredoxins
keywords: DFNB101; GRXCR2; Pakistan; deafness; moderate to severe; progressive