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

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Serval ID
serval:BIB_353FDBCB75A5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro.
Journal
Human Molecular Genetics
Author(s)
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.
ISSN
0964-6906 (Print)
ISSN-L
0964-6906
Publication state
Published
Issued date
2002
Volume
11
Number
23
Pages
2829-2836
Language
english
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.
Keywords
Animals, Binding Sites, Blotting, Western, DNA Mutational Analysis, DNA Primers/chemistry, Deafness/genetics, Deafness/metabolism, Endoplasmic Reticulum/metabolism, Epithelial Sodium Channel, Female, Genes, Recessive/genetics, Genotype, Humans, In Situ Hybridization, Male, Membrane Proteins/genetics, Membrane Proteins/metabolism, Mice, Mutation, Missense/genetics, Neoplasm Proteins/genetics, Neoplasm Proteins/metabolism, Oocytes/metabolism, Organ of Corti/metabolism, Protein Transport, RNA, Messenger/metabolism, Rabbits, Rats, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases/genetics, Serine Endopeptidases/metabolism, Sodium Channels/metabolism, Spiral Ganglion/metabolism, Stria Vascularis/metabolism, Xenopus laevis
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 13:00
Last modification date
01/10/2019 6:17
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