Human Genetics

, Volume 117, Issue 6, pp 528–535

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

Authors

  • Marie Wattenhofer
    • Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical School
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)CNRS/INSERM/Université Louis Pasteur
  • Nilüfer Sahin-Calapoglu
    • Department of Medical BiologyMedical School of Süleyman Demirel University
  • Ditte Andreasen
    • Pharmacology and Toxicology InstituteUniversity of Lausanne
  • Ersan Kalay
    • Department of Human GeneticsRadboud University Nijmegen Medical Centre
    • Department of OtorhinolaryngologyRadboud University Nijmegen Medical Centre
    • Department of Medical Biology, Faculty of MedicineKaradeniz Technical University
  • Refik Caylan
    • Department of Otorhinolaryngology, Faculty of Medicine Karadeniz Technical University
  • Bastien Braillard
    • Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical School
  • Nicole Fowler-Jaeger
    • Pharmacology and Toxicology InstituteUniversity of Lausanne
  • Alexandre Reymond
    • Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical School
    • Center for Integrative GenomicsUniversity of Lausanne
  • Bernard C. Rossier
    • Pharmacology and Toxicology InstituteUniversity of Lausanne
  • Ahmet Karaguzel
    • Department of Medical BiologyMedical School of Karadeniz Technical University
    • Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical School
Original Investigation

DOI: 10.1007/s00439-005-1332-x

Cite this article as:
Wattenhofer, M., Sahin-Calapoglu, N., Andreasen, D. et al. Hum Genet (2005) 117: 528. doi:10.1007/s00439-005-1332-x

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.

Copyright information

© Springer-Verlag 2005