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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    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 01/2015; 97:e4. DOI:10.1017/S001667231500004X · 2.20 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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    ABSTRACT: POU3F4 is a POU domain transcription factor that is required for hearing. In the ear, POU3F4 is essential for mesenchymal remodeling of the bony labyrinth and is the causative gene for DFNX2 human non-syndromic deafness. Ear abnormalities underlie this form of deafness, characterized previously in multiple spontaneous, radiation-induced and transgenic mouse mutants. Here we report three novel mutations in the POU3F4 gene that result in profound hearing loss in both humans and mice. A p.Gln79* mutation was identified in a child from an Israeli family, revealed by massively parallel sequencing (MPS). This strategy demonstrates the strength of MPS for diagnosis with only one affected individual. A second mutation, p.Ile285Argfs*43, was identified by Sanger sequencing. A p.Cys300* mutation was found in an ENU-induced mutant mouse, schwindel (sdl), by positional cloning. The mutation leads to a predicted truncated protein, similar to the human mutations, providing a relevant mouse model. The p.Ile285Argfs*43 and p.Cys300* mutations lead to a shift of Pou3f4 nuclear localization to the cytoplasm, demonstrated in cellular localization studies and in the inner ears of the mutant mice. The discovery of these mutations facilitates a deeper comprehension of the molecular basis of inner ear defects due to mutations in the POU3F4 transcription factor. © 2013 This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; 34(8). DOI:10.1002/humu.22339 · 5.05 Impact Factor
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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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    ABSTRACT: X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.
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