Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan

Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD, USA.
BMC Medical Genetics (Impact Factor: 2.08). 10/2004; 5(1):24. DOI: 10.1186/1471-2350-5-24
Source: PubMed


Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3.
We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3.
We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues.
Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.

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    • "The amino acid substitutions p.T340R and p.P431S both locate within TMPRSS3 protein serine protease domain. Data from the literature reveal that many other pathogenic mutations described in the TMPRSS3 gene are located in the same serine protease domain (Ahmed et al., 2004 "
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    ABSTRACT: Deafness is a really common disorder in humans. It can begin at any age with any degree of severity. Hereditary hearing loss is characterized by a vast genetic heterogeneity with more than 140 loci described in humans but only 65 genes so far identified. Families affected by hearing impairment would have real advantages from an early molecular diagnosis that is of primary relevance in genetic counseling. In this perspective, here we report a family-based approach employing Ion Torrent DNA sequencing technology to analyze coding and UTR regions of 96 genes related to hearing function and loss in a first series of 12 families coming from Italy and Qatar. Using this approach we were able to find the causative gene in 4 out of these 12 families (33%). In particular 5 novel alleles were identified in the following genes LOXHD1, TMPRSS3, TECTA and MYO15A already associated with hearing impairment. Our study confirms the usefulness of a targeted sequencing approach despite larger numbers are required for further validation and for defining a molecular epidemiology picture of hearing loss in these two countries.
    Gene 03/2014; 542(2). DOI:10.1016/j.gene.2014.03.033 · 2.14 Impact Factor
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    • "Twenty-two families with a mutation in TMPRSS3 had been reported previously (Shahin et al. 2010; Bonne-Tamir et al. 1996; Veske et al. 1996; Ben-Yosef et al. 2001; Masmoudi et al. 2001; Wattenhofer et al. 2002, 2005; Ahmed et al. 2004; Hutchin et al. 2005; Walsh et al. 2006; Elbracht et al. 2007; Table 3). Since the clinical data provided for most of these TMPRSS3 families are very limited, a thorough comparison with our data is not possible. "
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    ABSTRACT: In the present study, genotype–phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation. Electronic supplementary material The online version of this article (doi:10.1007/s10162-011-0282-3) contains supplementary material, which is available to authorized users.
    Journal of the Association for Research in Otolaryngology 07/2011; 12(6):753-66. DOI:10.1007/s10162-011-0282-3 · 2.60 Impact Factor
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    • "In addition, these membrane-spanning proteins have cytoplasmic N-terminal domains, suggesting possible functions in intracellular signal transduction [Wu, 2003]. Recently, we and others have shown that mutations in TMPRSS3 were responsible for both familial and sporadic forms of nonsyndromic recessive deafness [Ben-Yosef et al., 2001; Masmoudi et al., 2001; Scott et al., 2001; Wattenhofer et al., 2002, 2005; Ahmed et al., 2004; Hutchin et al., 2005]. Genes involved in deafness can be grouped into functional categories (ion channels, transcription factors, motor molecules, extracellular matrix components, and cytoskeletal components). "
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    ABSTRACT: Building on our discovery that mutations in the transmembrane serine protease, TMPRSS3, cause nonsyndromic deafness, we have investigated the contribution of other TMPRSS family members to the auditory function. To identify which of the 16 known TMPRSS genes had a strong likelihood of involvement in hearing function, three types of biological evidence were examined: 1) expression in inner ear tissues; 2) location in a genomic interval that contains a yet unidentified gene for deafness; and 3) evaluation of hearing status of any available Tmprss knockout mouse strains. This analysis demonstrated that, besides TMPRSS3, another TMPRSS gene was essential for hearing and, indeed, mice deficient for Hepsin (Hpn) also known as Tmprss1 exhibited profound hearing loss. In addition, TMPRSS2, TMPRSS5, and CORIN, also named TMPRSS10, showed strong likelihood of involvement based on their inner ear expression and mapping position within deafness loci PKSR7, DFNB24, and DFNB25, respectively. These four TMPRSS genes were then screened for mutations in affected members of the DFNB24 and DFNB25 deafness families, and in a cohort of 362 sporadic deaf cases. This large mutation screen revealed numerous novel sequence variations including three potential pathogenic mutations in the TMPRSS5 gene. The mutant forms of TMPRSS5 showed reduced or absent proteolytic activity. Subsequently, TMPRSS genes with evidence of involvement in deafness were further characterized, and their sites of expression were determined. Tmprss1, 3, and 5 proteins were detected in spiral ganglion neurons. Tmprss3 was also present in the organ of Corti. TMPRSS1 and 3 proteins appeared stably anchored to the endoplasmic reticulum membranes, whereas TMPRSS5 was also detected at the plasma membrane. Collectively, these results provide evidence that TMPRSS1 and TMPRSS3 play and TMPRSS5 may play important and specific roles in hearing.
    Human Mutation 01/2008; 29(1):130-41. DOI:10.1002/humu.20617 · 5.14 Impact Factor
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