title: An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss.
abstract: Building on our discovery that mutations in the transmembrane serine protease, TMPRSS3, cause nonsyndromic deafness, we have investigated the contribution of other TMPRSS family members to the auditory function. To identify which of the 16 known TMPRSS genes had a strong likelihood of involvement in hearing function, three types of biological evidence were examined: 1) expression in inner ear tissues; 2) location in a genomic interval that contains a yet unidentified gene for deafness; and 3) evaluation of hearing status of any available Tmprss knockout mouse strains. This analysis demonstrated that, besides TMPRSS3, another TMPRSS gene was essential for hearing and, indeed, mice deficient for Hepsin (Hpn) also known as Tmprss1 exhibited profound hearing loss. In addition, TMPRSS2, TMPRSS5, and CORIN, also named TMPRSS10, showed strong likelihood of involvement based on their inner ear expression and mapping position within deafness loci PKSR7, DFNB24, and DFNB25, respectively. These four TMPRSS genes were then screened for mutations in affected members of the DFNB24 and DFNB25 deafness families, and in a cohort of 362 sporadic deaf cases. This large mutation screen revealed numerous novel sequence variations including three potential pathogenic mutations in the TMPRSS5 gene. The mutant forms of TMPRSS5 showed reduced or absent proteolytic activity. Subsequently, TMPRSS genes with evidence of involvement in deafness were further characterized, and their sites of expression were determined. Tmprss1, 3, and 5 proteins were detected in spiral ganglion neurons. Tmprss3 was also present in the organ of Corti. TMPRSS1 and 3 proteins appeared stably anchored to the endoplasmic reticulum membranes, whereas TMPRSS5 was also detected at the plasma membrane. Collectively, these results provide evidence that TMPRSS1 and TMPRSS3 play and TMPRSS5 may play important and specific roles in hearing.
authors.affiliation: Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Min-Yen
authors.initials: MY
authors.lastname: Toh
authors.forename: Justin
authors.initials: J
authors.lastname: Tan
authors.forename: Daeho
authors.initials: D
authors.lastname: Park
authors.forename: Kelly
authors.initials: K
authors.lastname: Hanson
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.forename: David
authors.initials: D
authors.lastname: Kwong
authors.forename: Ping Z F
authors.initials: PZ
authors.lastname: Cannon
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.forename: Alex
authors.initials: A
authors.lastname: Gout
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Dahl
authors.forename: Michael
authors.initials: M
authors.lastname: Petersen
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Teasdale
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
mesh_terms: D000818:Animals; D007758:Ear, Inner / Q000378:metabolism; D034381:Hearing Loss / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human; C055645:hepsin