A Frameshift Mutation in GRXCR2 Causes Recessively Inherited Hearing Loss

Overview

Journal Hum Mutat

Specialty Genetics

Date 2014 Mar 13

PMID 24619944

Citations 28

Authors

Ayesha Imtiaz

David C Kohrman

Sadaf Naz

Affiliations

Soon will be listed here.

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.

Citing Articles

Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades.

Shadab M, Abbasi A, Ejaz A, Ben-Mahmoud A, Gupta V, Kim H J Cell Mol Med. 2024; 28(8):e18119.

PMID: 38534090 PMC: 10967143. DOI: 10.1111/jcmm.18119.

Critical role of TPRN rings in the stereocilia for hearing.

Qi J, Tan F, Zhang L, Zhou Y, Zhang Z, Sun Q Mol Ther. 2023; 32(1):204-217.

PMID: 37952086 PMC: 10787140. DOI: 10.1016/j.ymthe.2023.11.011.

Deafness gene screening based on a multilevel cascaded BPNN model.

Liu X, Teng L, Zuo W, Zhong S, Xu Y, Sun J BMC Bioinformatics. 2023; 24(1):56.

PMID: 36803022 PMC: 9942297. DOI: 10.1186/s12859-023-05182-7.

RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss.

Li J, Liu C, Muller U, Zhao B Dev Cell. 2022; 57(18):2204-2220.e6.

PMID: 36113482 PMC: 9529990. DOI: 10.1016/j.devcel.2022.08.011.

ARNSHL gene identification: past, present and future.

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