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

Department of Otorhinolaryngology, Head and Neck Surgery, Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.99). 05/2011; 88(5):628-34. DOI: 10.1016/j.ajhg.2011.04.012
Source: PubMed

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.

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Available from: Ronald Pennings, Aug 22, 2015
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    • "N/A c OSBPL2 IlluminaHiSeq (Xingetal.,2014) XNSHL a DFNX4 SMPX IlluminaGAIIx (Schradersetal.,2011;Huebneretal.,2011 "
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    • "Of these, an estimated 1%–5% of human hereditary hearing loss is caused by X-linked mutations in different populations [Petersen et al., 2008; Reardon, 1990]. To date, five deafness loci have been mapped to chromosome X, with three of the corresponding genes identified, PRPS1 for DFNX1 [Liu et al., 2010], POU3F4 for DFNX2 [de Kok et al., 1995], and SMPX for DFNX4 [Huebner et al., 2011; Schraders et al., 2011]. DFNX2 (MIM #304400) is the result of mutations in the POU3F4 (POU domain class 3, transcription factor 4, BRN-4) transcription factor that belongs to subclass III of the POU superfamily. "
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    • "The phenotype of the SMPX c.99delC carriers is similar to the phenotype of SMPX mutations carriers previously reported. [Huebner et al., 2011; Schraders et al., 2011; Weegerink et al., 2011] For example, males in previous studies of SMPX presented early, around 2 years of age, with bilateral slowly progressive hearing loss, whereas females with the same mutations showed a wide range of variability in the onset and severity of the disease much like that of the subjects observed in Families 2024 and 2196. This study has identified a novel founder mutation in exon 3 (c.99delC) of SMPX that cosegregates in two Newfoundland families , and supports the previous association of SMPX to the DFNX4 locus. "
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