A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein

Article Article scientifique Article A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein eng 2005 author Wattenhofer Marie author Sahin-Calapoglu Nilufer author Andreasen Ditte author Kalay Ersan author Caylan Refik author Braillard Bastien 540915 author Fowler-Jaeger Nicole author Reymond Alexandre 133817 author Rossier B. C. author Karaguzel Ahmet author Antonarakis Stylianos 22813 528-535 10.1007/s00439-005-1332-x 16021470 0340-6717 http://www.springerlink.com/content/w7l00g5p5838l032/fulltext.pdf 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. Amino Acid Sequence Chromosomes, Human, Pair 21 Deafness/ genetics Female Haplotypes Humans Linkage (Genetics) Lod Score Male Membrane Proteins/ genetics/metabolism Molecular Sequence Data Mutation, Missense Neoplasm Proteins/ genetics/metabolism Pedigree Serine Endopeptidases/ genetics/metabolism Dewey 616 Open Access - Licence nationale Springer 56 Département de médecine 221 false Human genetics 117 6 fef8fcd8-a0cc-42b2-af2d-0ffef6a7c031 Article (Published version) Public file1.pdf 397636 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein	Human genetics			2005	709	368

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Braillard, Bastien