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 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
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DOI：
10.1111/j.1399-0004.2007.00889.x
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发表时间：
2007-11-01
影响因子：
3.5
通讯作者：
Yuan, H. J.
中科院分区：
文献类型：
--
作者：
Cheng, J.;Han, D. Y.;Yuan, H. J.
我们在此报告一个非综合征型、迟发性常染色体显性感音神经性耳聋大家族的临床、遗传和分子特征。临床评估显示，这些受试者的听力损失在严重程度和发病年龄方面存在不同的表型。全基因组连锁分析将疾病基因定位到DFNA 5位点，对于标记D 7S 2457，在[theta] = 0处的最大两点对数优势分数为5.39。DFNA 5的DNA测序揭示了内含子8的剪接供体位点处的新的杂合IVS 8 +4 A > G取代。逆转录-聚合酶链反应（RT-PCR）显示突变体转录本中外显子8的跳跃。这种突变忠实地与家庭中的听力损失共分离。此外，该突变在100个无关的中国血统的对照DNA样本中不存在。预测IVS 8 +4 A > G突变在阅读框中产生移位并在位置372处引入终止密码子，从而导致过早截短的DFNA 5蛋白。迄今为止，共有四种DFNA 5突变被报道导致听力障碍，它们都导致mRNA水平上外显子8的跳跃。我们的研究结果进一步支持了DFNA 5相关听力损失是由一种非常特异的功能获得性突变引起的假设。
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.