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Dr Hamish S Scott
Genetics and Bioinformatics Division
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville, VIC, 3050
Email: hscott@wehi.edu.au
Tel: +61-3-9345 2484
Fax: +61-3-9347-0852
Homepage: http://www.mbgproject.org/SCOTT_LAB/SCOTT_Introduction.html

We are interested in understanding the role of type II transmembrane serine proteases (TTSPs) in physiological and pathological conditions using genetics and genomics approaches. Following our recent discovery that mutations in a novel TTSP (TMPRSS3) caused both familial and sporadic deafness, we have launched a number of studies investigating the role of TMPRSS3 and other TTSPs in deafness.
We and others have shown that TMPRSS3 mutants causing deafness were all defective in proteolytic activity suggesting that important molecular pathway(s) in the inner ear are controlled by TMPRSS3 mediated proteolytic cleavage. To characterize these pathways and the mechanism of deafness caused by the absence of TMPRSS3, potential physiological substrates (ENaC sodium channel and neurotrophins) for TMPRSS3 are currently under investigation and a Tmprss3 knockout mouse is being generated.
We are also looking whether other TTSPs are involved in hearing loss. Based on their expression profile in the inner ear (we have characterised the expression profile of 13 of the 16 known TTSPs in 20 tissues) and their mapping position to known loci of genetic deafness, 4 TTSP genes were prioritised for mutation analysis in deafness patients. One of the TTSP genes analysed has been found to be mutated in one deafness patients.
TTSP genes have already been implicated in various pathological processes (enteropeptidase deficiency, cancer and deafness) and our expression profile data demonstrated restricted expression profile for most TTSPs suggesting tissue specific functions and potential roles in various pathological processes. We are interested to look at potential roles of selected candidate TTSP in a various diseases using a semi high throughput mutations analysis in affected patients.
We are also interested to know whether TTSP knockout exhibit hearing defects and will soon be testing the hearing of hepsin knock out mice (collaboration with Dr. Qingyu Wu).
Dr Qingyu Wu
Department of Cardiovascular Research, Berlex Biosciences Richmond California
Project: Investigation for hearing defects in the hepsin KO mouse

Dr Woo Jin Park
Department of Life Science and National Research laboratory of Proteolysis, Kwangju Institute of Science and Technology, Kangju, Korea
Project: Investigation of the proteolytic activity of TTSP proteins containing pathogenic mutations or polymorphisms using a yeast-based protease assay.
Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S, Minoshima S, Younus F, Mehdi SQ, Radhakrishna U, Papasavvas MP, Gehrig C, Rossier C, Korostishevsky M, Gal A, Shimizu N, Bonne-Tamir B, Antonarakis SE.
Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet. 2001 Jan;27(1):59-63.

Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U, Naz S, Ahmed Z, Riazuddin S, Pandya A, Nance WE, Wilcox ER, Friedman TB, Morell RJ.
Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. J Med Genet. 2001 Jun;38(6):396-400.

Masmoudi S, Antonarakis SE, Schwede T, Ghorbel AM, Gratri M, Pappasavas MP, Drira M, Elgaied-Boulila A, Wattenhofer M, Rossier C, Scott HS, Ayadi H, Guipponi M. Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non-syndromic autosomal recessive deafness. Hum Mutat. 2001 Aug;18(2):101-8.

Wattenhofer M, Di Iorio MV, Rabionet R, Dougherty L, Pampanos A, Schwede T, Montserrat-Sentis B, Arbones ML, Iliades T, Pasquadibisceglie A, D'Amelio M, Alwan S, Rossier C, Dahl HH, Petersen MB, Estivill X, Gasparini P, Scott HS, Antonarakis SE.
Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. J Mol Med. 2002 Feb;80(2):124-31

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 PL, Kudoh J, Shimizu N, Scott HS, Antonarakis SE, Rossier BC.
The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet. 2002 Nov 1;11(23):2829-36.

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