Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse
ABSTRACT Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells.
SourceAvailable from: Nicolas Daudet[Show abstract] [Hide abstract]
ABSTRACT: Hearing relies on the mechanosensory inner and outer hair cells of the organ of Corti, which convert mechanical deflections of their actin-rich stereociliary bundles into electrochemical signals. Several actin-associated proteins are essential for stereocilia formation and maintenance, and their absence leads to deafness. One of the most abundant actin-bundling proteins of stereocilia is plastin 1, but its function has never been directly assessed. Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies. Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length. The stereocilia of outer hair cells were comparatively less affected, however they also showed signs of degeneration in ageing mice. The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size, of the mechanoelectrical transducer currents. These results show that in contrast to other actin-bundling proteins such as espin, harmonin, or Eps8, plastin 1 is dispensable for the initial formation of stereocilia. However the progressive hearing loss and morphological defects of hair cells in adult Pls1 KO mice point at a specific role for plastin 1 in the preservation of adult stereocilia and optimal hearing. Hence, mutations in the human PLS1 gene may be associated to relatively mild and progressive forms of hearing loss.Human Molecular Genetics 08/2014; DOI:10.1093/hmg/ddu417 · 6.68 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Hearing impairment is the most common sensory disorder, present 1 in every 500 newborns. About 80% of genetic HL is classified as non-syndromic deafness. To date, over 115 non-syndromic loci have been identified of which fifty associated with autosomal recessive non-syndromic hearing loss (ARNSHL). In this review article, we represent the 40 genes function and contribution to genetic deafness in different Middle Eastern populations as well as gene frequencies and mutation spectrum. The vide variety of mutations have so far detected in 19 countries reflects the heterogeneity of the genes involved in HL in this region. The deafness genes can cause dysfunction of cochlear homeostasis, cellular organization, neuronal transmission, cell growth, differentiation, and survival, some coding for tectorial membrane-associated proteins, and the remaining with unknown functions. Non-syndromic deafness is highly heterogeneous and mutations in the GJB2 are responsible for almost 30-50% in northwest to as low as 0 to 5% in south and southeast of the Middle East, it remain as major gene in ARNSHL in Middle East. The other genes contributing to AR/ADNSHL in some countries has been determined while for many other countries in the Middle East has not been studied or little study has been done. With the advancement of next generation sequencing one could expect in next coming year many of the remaining genes to be determine and to understand their function in the inner ear.International Journal of Pediatric Otorhinolaryngology 09/2014; 78(12). DOI:10.1016/j.ijporl.2014.08.036 · 1.32 Impact Factor
[Show abstract] [Hide abstract]
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. This article is protected by copyright. All rights reservedHuman Mutation 05/2014; 35(5). DOI:10.1002/humu.22545 · 5.05 Impact Factor