title: Novel TMPRSS3 variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.
abstract: Mutations in the TMPRSS3 gene are known to cause autosomal recessive non-syndromic hearing impairment (ARNSHI). After undergoing a genome scan, 10 consanguineous Pakistani families with ARNSHI were found to have significant or suggestive evidence of linkage to the TMPRSS3 region. In order to elucidate if the TMPRSS3 gene is responsible for ARNSHI in these families, the gene was sequenced using DNA samples from these families. Six TMPRSS3 variants were found to cosegregate in 10 families. None of these variants were detected in 500 control chromosomes. Four novel variants, three of which are missense [c.310G>A (p.Glu104Lys), c.767C>T (p.Ala256Val) and c.1273T>C (p.Cys425Arg)] and one nonsense [c.310G>T (p.Glu104Stop)], were identified. The pathogenicity of novel missense variants was investigated through bioinformatics analyses. Additionally, the previously reported deletion c.208delC (p.His70ThrfsX19) was identified in one family and the known mutation c.1219T>C (p.Cys407Arg) was found in five families, which makes c.1219T>C (p.Cys407Arg) as the most common TMPRSS3 mutation within the Pakistani population. Identification of these novel variants lends support to the importance of elements within the low-density lipoprotein receptor A (LDLRA) and serine protease domains in structural stability, ligand binding and proteolytic activity for proper TMPRSS3 function within the inner ear.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza 700DE,Houston, TX 77030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: A
authors.initials: A
authors.lastname: Islam
authors.forename: M
authors.initials: M
authors.lastname: Ansar
authors.forename: P B
authors.initials: PB
authors.lastname: Andrade
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: R L P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.forename: W
authors.initials: W
authors.lastname: Ahmad
authors.forename: S M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D016022:Case-Control Studies; D002891:Chromosomes, Human, Pair 21; D003241:Consanguinity; D007758:Ear, Inner / Q000201:enzymology / Q000473:pathology*; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D034381:Hearing Loss / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human