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Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness
  1. Tamar Ben-Yosefa,
  2. Marie Wattenhoferb,d,
  3. Saima Riazuddina,c,c,
  4. Zubair M Ahmeda,c,c,
  5. Hamish S Scott*,d,
  6. Jun Kudohe,
  7. Kazunori Shibuyae,
  8. Stylianos E Antonarakisd,
  9. Batsheva Bonne-Tamirf,
  10. Uppala Radhakrishnad,
  11. Sadaf Nazc,
  12. Zahoor Ahmeda,c,c,
  13. Sheikh Riazuddina,c,c,
  14. Arti Pandyag,
  15. Walter E Nanceg,
  16. Edward R Wilcoxa,
  17. Thomas B Friedmana,
  18. Robert J Morella
  1. aLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA, bGraduate Program of Molecular and Cellular Biology, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva, Switzerland, cCentre of Excellence in Molecular Biology, Punjab University, Lahore, Pakistan, dDivision of Medical Genetics, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva, Switzerland, eDepartment of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, fDepartment of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel-Aviv University, 69978 Ramat-Aviv, Israel, gDepartment of Human Genetics, Virginia Commonwealth University, Richmond 23298-0033, USA
  1. Dr Friedman, 5 Research Court, Room 2A-19, NIDCD/NIH, Rockville, MD 20850, USA, friedman{at}nidcd.nih.gov

https://doi.org/10.1136/jmg.38.6.396

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    Editor—Congenital deafness occurs in approximately 1 in 1000 live births and 50% of these cases are hereditary. Non-syndromic deafness is classified according to its mode of inheritance as DFN, DFNA, and DFNB (X linked, autosomal dominant, and autosomal recessive, respectively). Non-syndromic recessive deafness accounts for ∼80% of congenital hereditary deafness cases.1 At least 30 DFNB loci have been mapped in the past few years by genetic linkage studies, but the causative gene has been identified for only eight of these loci2-4 (Hereditary Hearing Loss Homepage, http://www.uia.ac.be/dnalab/hhh).

    Two of the previously reported loci for non-syndromic recessive deafness are DFNB8 and DFNB10, both located on chromosome 21q22.3 (MIM 601072 and 605316). The DFNB8 locus was originally identified in a large consanguineous Pakistani family, segregating childhood onset deafness,5 while DFNB10 was identified in a large consanguineous Palestinian family, in which deafness was congenital.6 Recently, theTMPRSS3 gene was shown to be mutated in affected subjects of both families.7

    TMPRSS3 belongs to a family of transmembrane serine proteases, also including TMPRSS1,8 TMPRSS2,9 and TMPRSS4.10 The TMPRSS3 gene extends over 24 kb and comprises 13 exons. It has four alternative transcripts (TMPRSS3 a,b, c, andd), encoding putative peptides of 454, 327, 327, and 344 amino acids, respectively.7 TMPRSS3a, which contains all 13 exons, is the most abundant transcript and its expression could be detected in various tissues, including fetal cochlea.7 In addition to the serine protease and the transmembrane domains,TMPRSS3 also encodes low density lipoprotein receptor class A (LDLRA) and scavenger receptor cysteine rich (SRCR) domains, which are potentially involved in binding with extracellular molecules and/or the cell surface.7

    Material and methods

    To identify DFNB8/B10 linked families, we analysed a total of 159 consanguineous Pakistani families that …

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