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  • Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3

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Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3
  1. Y J Lee,
  2. D Park,
  3. S Y Kim,
  4. W J Park
  1. Department of Life Science and National Research Laboratory of Proteolysis, Kwangju Institute of Science and Technology (K-JIST), Kwangju, Korea
  1. Correspondence to:
 Dr W J Park, Department of Life Science, Kwangju Institute of Science and Technology (K-JIST), 1 Oryong-dong, Puk-gu, Kwangju, 500-712 Korea; 
 wjpark{at}kjist.ac.kr

https://doi.org/10.1136/jmg.40.8.629

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    Congenital hearing loss occurs in approximately 1 in 1000 live births and 60% of these cases are hereditary.1,2 Non-syndromic autosomal recessive deafness accounts for about 70% of congenital hereditary hearing loss cases. To date, at least 33 genetic loci have been mapped for non-syndromic deafness, and the causative genes for 17 of these loci have been identified.3 Mutations in the TMPRSS3 gene, which encodes a transmembrane serine protease, were originally identified in Pakistani DFNB8 and Palestinian DFNB10 families, and later in two Tunisian families and several white patients.4–9

    TMPRSS3 belongs to a family of transmembrane serine proteases, which includes TMPRSS1-5.5,10 Like the other members of this family, TMPRSS3 contains a short amino terminus, a transmembrane domain and a large extracellular or lumenal carboxyl terminal segment characterised by a stem region containing LDLRA (low density lipoprotein receptor class A), SRCR (scavenger receptor cysteine rich) domains, and a catalytic domain. In addition to a deleterious β-satellite repeat insertion and splice acceptor site substitution,6 six pathogenic missense mutations have been isolated.7 Since these mutations occur not only in the catalytic domain, but also in the LDLRA and SRCR domains involved in interactions with extracellular molecules, the molecular mechanism for pathogenesis is unclear. In this study, we determine whether these missense mutations affect the proteolytic activity of TMPRSS3.

    Key points

    • Mutations in the TMPRSS3 gene, which encodes a transmembrane serine protease, are responsible for non-syndromic autosomal recessive deafness, DFNB8 and 10. Pathogenic mutations were found in the LDLRA (low density lipoprotein receptor class A) and SRCR (scavenger receptor cysteine rich) domains as well as the serine protease domain.

    • We have assayed the proteolytic activity of the TMPRSS3 proteins containing pathogenic mutations or polymorphisms …

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