Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

Abstract

In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both.

Variable degrees of hearing impairment in a Dutch DFNX4 (DFN6) family

“…Only 1e5% of cases with non-syndromic hereditary hearing impairment exhibit X-linked inheritance. In syndromic hearing impairment Xlinked inheritance is seen far more often (Smith and Van Camp, 2008).…”

Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6

“…1 Only three genes have been associated with X-linked nonsyndromic hearing loss until now: PRPS1 (MIM 311850; DFNX1, formerly DFN2) on Xq22 that encodes phosphoribosyl pyrophosphate synthetase 1, 6 POU3F4 (MIM 300039; DFNX2, formerly DFN3) on Xq21, encoding a member of a transcription factor family that contains a POU domain 7 and the recently identified gene for the small muscle protein, X-linked (SMPX; MIM 300226) on Xp22, accounting for DFNX4 (formerly DFN6). 8,9 An additional locus has been mapped to the short arm of the X chromosome (DFNX3, formerly DFN4) overlapping with the DMD locus on Xp21.2. 10,11 Here, we present data on a Hungarian family in which only male subjects suffer from severe congenital hearing loss, whereas female subjects are not or only mildly to moderately affected.…”

Non-syndromic hereditary sensorineural hearing loss: review of the genes involved

“…23 The X-linked gene SMPX (DFN4) encodes a protein suggested to have a function in stereocilial development and maintenance in response to the repetitive mechanical stress that these stereocilia are subjected to. 24,25 The protein espin acts as a bundling protein, providing stability to the stereocilial cytoskeleton. 26 In 'jerker' mice that lack espin, stereocilia shorten and merge from postnatal day 11, which is simultaneous with the onset of hearing.…”