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

Michel Guipponi, Grégoire Vuagniaux, Marie Wattenhofer, Kazunori Shibuya, Maria Vazquez, Loretta Dougherty, Nathalie Scamuffa, Elizabeth Guida, Michiyo Okui, Colette Rossier, Manuela Hancock, Karine Buchet, Alexandre Reymond, Edith Hummler, Philip L. Marzella, Jun Kudoh, Nobuyoshi Shimizu, Hamish S. Scott, Stylianos E. Antonarakis, Bernard C. Rossier

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2829-2836
Number of pages8
JournalHuman molecular genetics
Volume11
Issue number23
DOIs
Publication statusPublished - 2002 Nov 1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Guipponi, M., Vuagniaux, G., Wattenhofer, M., Shibuya, K., Vazquez, M., Dougherty, L., Scamuffa, N., Guida, E., Okui, M., Rossier, C., Hancock, M., Buchet, K., Reymond, A., Hummler, E., Marzella, P. L., Kudoh, J., Shimizu, N., Scott, H. S., Antonarakis, S. E., & Rossier, B. C. (2002). The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Human molecular genetics, 11(23), 2829-2836. https://doi.org/10.1093/hmg/11.23.2829