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Human Molecular Genetics, 2002, Vol. 11, No. 23 2829-2836
© 2002 Oxford University Press

The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro

Michel Guipponi1,{dagger},{ddagger}, Grégoire Vuagniaux2,{ddagger}, Marie Wattenhofer1,3, Kazunori Shibuya4, Maria Vazquez5, Loretta Dougherty6, Nathalie Scamuffa1, Elizabeth Guida7, Michiyo Okui4, Colette Rossier1, Manuela Hancock6, Karine Buchet1, Alexandre Reymond1, Edith Hummler2, Phillip L. Marzella7, Jun Kudoh4, Nobuyoshi Shimizu4, Hamish S. Scott6, Stylianos E. Antonarakis1,* and Bernard C. Rossier2

1Division of Medical Genetics, University of Geneva Medical School, and Geneva University Hospitals, Switzerland, 2Institut de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland, 3Graduate Program of Molecular and Cellular Biology, University of Geneva Medical School, Geneva, Switzerland, 4Department of Molecular Biology, Keio University School of Medecine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, 5Department of Morphology, University of Geneva Medical School, Geneva, Switzerland, 6Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, P.O. Royal Melbourne Hospital, Victoria 3050, Australia and 7Department of Otolaryngology, The University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria 3050, Australia

Received June 6, 2002; Accepted August 26, 2002

TMPRSS3 encodes a transmembrane serine protease that contains both LDLRA and SRCR domains and is mutated in non-syndromic autosomal recessive deafness (DFNB8/10). To study its function, we cloned the mouse ortholog which maps to Mmu17, which is structurally similar to the human gene and encodes a polypeptide with 88% identity to the human protein. RT–PCR and RNA in situ hybridization on rat and mouse cochlea revealed that Tmprss3 is expressed in the spiral ganglion, the cells supporting the organ of Corti and the stria vascularis. RT–PCR on mouse tissues showed expression in the thymus, stomach, testis and E19 embryos. Transient expression of wild-type or tagged TMPRSS3 protein showed a primary localization in the endoplasmic reticulum. The epithelial amiloride-sensitive sodium channel (ENaC), which is expressed in many sodium-reabsorbing tissues including the inner ear and is regulated by membrane-bound channel activating serine proteases (CAPs), is a potential substrate of TMPRSS3. In the Xenopus oocyte expression system, proteolytic processing of TMPRSS3 was associated with increased ENaC mediated currents. In contrast, 6 TMPRSS3 mutants (D103G, R109W, C194F, W251C, P404L, C407R) causing deafness and a mutant in the catalytic triad of TMPRSS3 (S401A), failed to undergo proteolytic cleavage and activate ENaC. These data indicate that important signaling pathways in the inner ear are controlled by proteolytic cleavage and suggest: (i) the existence of an auto-catalytic processing by which TMPRSS3 would become active, and (ii) that ENaC could be a substrate of TMPRSS3 in the inner ear.

* To whom correspondence should be addressed at: Division of Medical Genetics, Centre Médical Universitaire, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Tel: +41 227025708; Fax: +41 227025706; Email: stylianos.antonarakis{at}medecine.unige.ch

{dagger} Present address: Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, P.O. Royal Melbourne Hospital, Victoria 3050, Australia.

{ddagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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