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: 10.93). 05/2011; 88(5):628-34. DOI: 10.1016/j.ajhg.2011.04.012
Source: PubMed


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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    • "N/A c OSBPL2 IlluminaHiSeq (Xingetal.,2014) XNSHL a DFNX4 SMPX IlluminaGAIIx (Schradersetal.,2011;Huebneretal.,2011 "
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    ABSTRACT: Next-generation sequencing (NGS) technologies have played a central role in the genetic revolution. These technologies, especially whole-exome sequencing, have become the primary tool of geneticists to identify the causative DNA variants in Mendelian disorders, including hereditary deafness. Current research estimates that 1% of all human genes have a function in hearing. To date, mutations in over 80 genes have been reported to cause nonsyndromic hearing loss (NSHL). Strikingly, more than a quarter of all known genes related to NSHL were discovered in the past 5 years via NGS technologies. In this article, we review recent developments in the usage of NGS for hereditary deafness, with an emphasis on whole-exome sequencing.
    Genetics Research 03/2015; 97:e4. DOI:10.1017/S001667231500004X · 1.47 Impact Factor
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    • "Interestingly, SPMX might play an important role in another tissue that relies on mechanotransduction, namely the auditory system. Huebner et al. suggest that SMPX plays a critical role in protecting against mechanical stress in cells in the organ of Corti as nonsense mutations in the Smpx gene results in hearing loss in humans [23], [24]. The fact that Rac1, a GTPase activated by biomechanichal stress, is a major target for SMPX [13] supports its role as a possible mechanotransducer. "
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    ABSTRACT: Mechanical factors such as stretch are thought to be important in the regulation of muscle phenotype. Small muscle protein X-linked (SMPX) is upregulated by stretch in skeletal muscle and has been suggested to serve both as a transcription factor and a mechanosensor, possibly giving rise to changes in both fiber size and fiber type. We have used in vivo confocal imaging to study the subcellular localization of SMPX in skeletal muscle fibers of adult rats using a SMPX-EGFP fusion protein. The fusion protein was localized predominantly in repetitive double stripes flanking the Z-disc, and was excluded from all nuclei. This localization would be consistent with SMPX being a mechanoreceptor, but not with SMPX playing a role as a transcription factor. In vivo overexpression of ectopic SMPX in skeletal muscle of adult mice gave no significant changes in fiber type distribution or cross sectional area, thus a role of SMPX in regulating muscle phenotype remains unclear.
    PLoS ONE 06/2014; 9(6):e99232. DOI:10.1371/journal.pone.0099232 · 3.23 Impact Factor
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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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