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|Title:||An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss|
|Citation:||Human Mutation, 2008; 29(1):130-141|
|Michel Guipponi, Min-Yen Toh, Justin Tan, Daeho Park, Kelly Hanson, Ester Ballana, David Kwong, Ping Z.F. Cannon, Qingyu Wu, Alex Gout, Mauro Delorenzi, Terence P. Speed, Richard J.H. Smith, Henrik H. Dahl, Michael Petersen, Rohan D. Teasdale, Xavier Estivill, Woo Jin Park and Hamish S. Scott|
|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.|
|Keywords:||Animals; Mice, Knockout; Humans; Mice; Hearing Loss; Serine Endopeptidases; Membrane Proteins; Neoplasm Proteins; Immunohistochemistry; Mutation; Ear, Inner|
|Description:||The definitive version may be found at www.wiley.com|
|Appears in Collections:||Medicine publications|
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