Abstract
Pathogenic mutations in TMPRSS3, which encodes a transmembrane serine protease, cause non-syndromic deafness DFNB8/10. Missense mutations map in the low density-lipoprotein receptor A (LDLRA), scavenger-receptor cysteine-rich (SRCR), and protease domains of the protein, indicating that all domains are important for its function. TMPRSS3 undergoes proteolytic cleavage and activates the ENaC sodium channel in a Xenopus oocyte model system. To assess the importance of this gene in non-syndromic childhood or congenital deafness in Turkey, we screened for mutations affected members of 25 unrelated Turkish families. The three families with the highest LOD score for linkage to chromosome 21q22.3 were shown to harbor P404L, R216L, or Q398X mutations, suggesting that mutations in TMPRSS3 are a considerable contributor to non-syndromic deafness in the Turkish population. The mutant TMPRSS3 harboring the novel R216L missense mutation within the predicted cleavage site of the protein fails to undergo proteolytic cleavage and is unable to activate ENaC, thus providing evidence that pre-cleavage of TMPRSS3 is mandatory for normal function.
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Acknowledgements
We thank the families and the administrative bodies of the schools for the deaf for their kind participation in this study. We also thank N. Akarsu, J.-L. Blouin, I. Bouchardy, C. Borel, Ö. Refik Çaylan, L. Excoffier, M. Friedli, M. Gagnebin, J.-D. Horisberger, E. Kalay, N. Lin-Marq, M. Morris, L. Pignat, C. Rossier and J.D. Vassali for critical comments, helpful discussions, or technical assistance. This work was supported by grants from the Swiss National Science Foundation (31.57149.99), the European Union (QLRT-2001-00816), the NCCR frontiers in Genetics, the Jérôme Lejeune Foundation, the Child Care Foundation to AR and SEA, from the Swiss National Science Foundation (31-061966.00) and the Danish Research Council (22-05-0535) to BR and DA. BB was supported by the Geneva Research Programme for Medical Students (PREM). This study was supported by the Karadeniz Technical University Research Fund (Project no: 2002.114.001.3), Stichting Irene Kinderziekenhuis and Stichting Vrienden van Effatha.
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Marie Wattenhofer and Nilüfer Sahin-Calapoglu contributed equally to this work
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Wattenhofer, M., Sahin-Calapoglu, N., Andreasen, D. et al. A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. Hum Genet 117, 528–535 (2005). https://doi.org/10.1007/s00439-005-1332-x
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DOI: https://doi.org/10.1007/s00439-005-1332-x