A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family

A. B. Cheng, D. Y. Han, P. Dai, H. J. Sun, R. Tao, Q. Sun, C. Yan, C. Qin, H. Y. Wang, X. M. Ouyang, S. Z. Yang, J. Y. Cao, G. Y. Feng, L. L. Du, Y. Z. Zhang, S. Q. Zhai, W. Y. Yang, X. Z. Liu, L. He, Hui Jun Yuan

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.

Original languageEnglish (US)
Pages (from-to)471-477
Number of pages7
JournalClinical Genetics
Volume72
Issue number5
DOIs
StatePublished - Nov 2007

Keywords

  • DFNA5
  • Hearing loss
  • Linkage analysis
  • Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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