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

作者：Cheng, J; Han, D Y; Dai, P; Sun, H J; Tao, R; Sun, Q; Yan, D; Qin, W; Wang, H Y; Ouyang, X M; Yang, S Z; Cao, J Y; Feng, G Y; Du, L L; Zhang, Y Z; Zhai, S Q; Yang, W Y; Liu, X Z; He, L; Yuan, H J^*

来源：Clinical Genetics, 2007, 72(5): 471-477.

DOI：10.1111/j.1399-0004.2007.00889.x

• DFNA5
• hearing loss
• linkage analysis
• mutation

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.

• 出版日期2007-11
• 单位中国人民解放军总医院; 上海交通大学; 四川大学