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

  • Marie Wattenhofer
  • Nilüfer Sahin-Calapoglu
  • Ditte Andreasen
  • Ersan Kalay
  • Refik Caylan
  • Bastien Braillard
  • Nicole Fowler-Jaeger
  • Alexandre Reymond
  • Bernard C. Rossier
  • Ahmet Karaguzel
  • Stylianos E. Antonarakis
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

Authors and Affiliations

  • Marie Wattenhofer
    • 1
    • 10
  • Nilüfer Sahin-Calapoglu
    • 2
  • Ditte Andreasen
    • 3
  • Ersan Kalay
    • 4
    • 5
    • 6
  • Refik Caylan
    • 7
  • Bastien Braillard
    • 1
  • Nicole Fowler-Jaeger
    • 3
  • Alexandre Reymond
    • 1
    • 8
  • Bernard C. Rossier
    • 3
  • Ahmet Karaguzel
    • 9
  • Stylianos E. Antonarakis
    • 1
  1. 1.Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical SchoolGenevaSwitzerland
  2. 2.Department of Medical BiologyMedical School of Süleyman Demirel UniversityIspartaTurkey
  3. 3.Pharmacology and Toxicology InstituteUniversity of LausanneSwitzerland
  4. 4.Department of Human GeneticsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  5. 5.Department of OtorhinolaryngologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  6. 6.Department of Medical Biology, Faculty of MedicineKaradeniz Technical UniversityTrabzonTurkey
  7. 7.Department of Otorhinolaryngology, Faculty of Medicine Karadeniz Technical UniversityTrabzonTurkey
  8. 8.Center for Integrative GenomicsUniversity of LausanneSwitzerland
  9. 9.Department of Medical BiologyMedical School of Karadeniz Technical UniversityTrabzonTurkey
  10. 10.Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)CNRS/INSERM/Université Louis PasteurCU de StrasbourgFrance