title: Novel CLDN14 mutations in Pakistani families with autosomal recessive non-syndromic hearing loss.
abstract: Mutations in the CLDN14 gene are known to cause autosomal recessive (AR) non-sydromic hearing loss (NSHL) at the DFNB29 locus on chromosome 21q22.13. As part of an ongoing study to localize and identify NSHL genes, the ARNSHL segregating in four Pakistani consanguineous families were mapped to the 21q22.13 region with either established or suggestive linkage. Given the known involvement of CLDN14 gene in NSHL, DNA samples from hearing-impaired members from the four families were sequenced to potentially identify causal variants within this gene. Three novel CLDN14 mutations, c.167G>A (p.Trp56*), c.242G>A (p.Arg81His), and c.694G>A (p.Gly232Arg), segregate with hearing loss (HL) in three of the families. The previously reported CLDN14 mutation c.254T>A (p.Val85Asp) was observed in the fourth family. None of the mutations were detected in 400 Pakistani control chromosomes and all were deemed damaging based on bioinformatics analyses. The non-sense mutation c.167G>A (p.Trp56*) is the first stop codon mutation in CLDN14 gene to be identified to cause NSHL. The c.242G>A (p.Arg81His) and c.694G>A (p.Gly232Arg) mutations were identified within the first extracellular loop and the carboxyl-tail of claudin-14, respectively, which highlights the importance of the extracellular domains and phosphorylation of cytoplasmic tail residues to claudin function within the inner ear. The HL due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Paula B
authors.initials: PB
authors.lastname: Andrade
authors.forename: Bushra
authors.initials: B
authors.lastname: Khan
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D057167:Claudins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D057167:Claudins; C422064:claudin 14