| Summary: | <p>Abstract</p> <p>Background</p> <p>Mutant alleles of <it>TMPRSS3 </it>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 <it>TMPRSS3 </it>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 <it>TMPRSS3</it>.</p> <p>Methods</p> <p>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 <it>TMPRSS3</it>. The structure of <it>TMPRSS3 </it>was characterized bioinformatically and experimentally by sequencing novel cDNA clones of <it>TMPRSS3</it>.</p> <p>Results</p> <p>We identified mutations in <it>TMPRSS3 </it>in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of <it>TMPRSS3 </it>segregating in a six-generation extended family from Newfoundland. The spectrum of <it>TMPRSS3 </it>mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of <it>TMPRSS3 </it>with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues.</p> <p>Conclusion</p> <p>Mutations of <it>TMPRSS3 </it>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 <it>TMPRSS3 </it>isoform <it>e </it>will be helpful in the functional characterization of the full length protein.</p>
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