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

• DOI: 10.1007/s00439-005-1332-x
• Publication Date: 2005-07-13T10:36:24Z
• Authors: Marie Wattenhofer; Nilüfer Sahin-Cal...; Ditte Andreasen; Ersan Kalay; Refik Caylan; Bastien Braillard; Nicole Fowler-Jaeger; Alexandre Reymond; Bernard C. Rossier; Ahmet Karaguzel; Stylianos E. Anto...
• Keywords: Male; Membrane Proteins/ genetics/metabolism; Chromosomes, Human, Pair 21; Genetic Linkage; DCN 2: Functional Neurogenomics; Molecular Sequence Data; Mutation, Missense; Deafness; 03 medical and health sciences; Neoplasm Proteins/ genetics/metabolism; info:eu-repo/classification/ddc/616; UMCN 3.3: Neurosensory disorders; Humans; Deafness/ genetics; Amino Acid Sequence; ddc:616; 0303 health sciences; Serine Endopeptidases; Linkage (Genetics); Membrane Proteins; Neoplasm Proteins; Pedigree; Haplotypes; Serine Endopeptidases/ genetics/metabolism; Female; Lod Score

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.