title: Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non-syndromic autosomal recessive deafness.
abstract: Recently the TMPRSS3 gene, which encodes a transmembrane serine protease, was found to be responsible for two non-syndromic recessive deafness loci located on human chromosome 21q22.3, DFNB8 and DFNB10. We found evidence for linkage to the DFNB8/10 locus in two unrelated consanguineous Tunisian families segregating congenital autosomal recessive sensorineural deafness. The audiometric tests showed a loss of hearing greater than 70 dB, in all affected individuals of both families. Mutation screening of TMPRSS3 revealed two novel missense mutations, W251C and P404L, altering highly conserved amino acids of the serine protease domain. Both mutations were not found in 200 control Tunisian chromosomes. The detection of naturally-occurring TMPRSS3 missense mutations in deafness families identifies functionally important amino acids. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C might lead to a structural rearrangement affecting the active site H257 and that P404L might alter the geometry of the active site loop and therefore affect the serine protease activity.
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine, Sfax, Tunisie.
authors.forename: S
authors.initials: S
authors.lastname: Masmoudi
authors.forename: S E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: T
authors.initials: T
authors.lastname: Schwede
authors.forename: A M
authors.initials: AM
authors.lastname: Ghorbel
authors.forename: M
authors.initials: M
authors.lastname: Gratri
authors.forename: M P
authors.initials: MP
authors.lastname: Pappasavas
authors.forename: M
authors.initials: M
authors.lastname: Drira
authors.forename: A
authors.initials: A
authors.lastname: Elgaied-Boulila
authors.forename: M
authors.initials: M
authors.lastname: Wattenhofer
authors.forename: C
authors.initials: C
authors.lastname: Rossier
authors.forename: H S
authors.initials: HS
authors.lastname: Scott
authors.forename: H
authors.initials: H
authors.lastname: Ayadi
authors.forename: M
authors.initials: M
authors.lastname: Guipponi
mesh_terms: D000595:Amino Acid Sequence; D001299:Audiometry; D001483:Base Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D003241:Consanguinity; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009363:Neoplasm Proteins; D010375:Pedigree; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics*; D014416:Tunisia
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human