Non-syndromic low-frequency sensorineural hearing loss （LFSNHL） is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPHI and WFS...Non-syndromic low-frequency sensorineural hearing loss （LFSNHL） is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPHI and WFSI, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C〉T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin （WFS 1）. In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7--50 years of age, with LFSNHL. We detected a heterozygous c.2108G〉A substitution in exon 8 of WFSI, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog （Xenopus）, Sequence analysis demonstrated the absence of c.2086C〉T or c.210gG〉A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL.展开更多
基金supported by the National High Technology Research and Development Program of China(863 Program) to Huijun Yuan(No.2007AA02E466)Key Project of National Natural Science Foundation of China to Huijun Yuan (No.81030017)and to Pu Dai(No.30872862)
文摘Non-syndromic low-frequency sensorineural hearing loss （LFSNHL） is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPHI and WFSI, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C〉T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin （WFS 1）. In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7--50 years of age, with LFSNHL. We detected a heterozygous c.2108G〉A substitution in exon 8 of WFSI, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog （Xenopus）, Sequence analysis demonstrated the absence of c.2086C〉T or c.210gG〉A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL.
