Identification of a novel DFNA5 mutation, IVS7-2 a > G, in a Chinese family with non-syndromic sensorineural hearing loss

Abstract

Background

To date, seven DFNA5 mutations have been reported in families with autosomal dominant non-syndromic hearing loss worldwide. All the mutations cause exon 8 skipping at the mRNA level, that led to the protein truncated and the protein could exert a gain of ototoxic function.

Objective

In this study, we found an autosomal-dominant non-syndromic hearing loss Chinese pedigree which spanned four generations and comprised 43 members. We want to identify the causative gene and mutation.

Methods

Application of microsatellite markers on DFNA 23 loci preliminary screening of 25 genes, data were analyzed by linkage analysis.

Results

We mapped the locus to the region between D7S629 and D7S516 (two-point lod-score of 5.39) with the application of 8 microsatellite markers. By direct sequencing of candidate genes in mapping region, we identified a novel missense mutation ivs7-2 A > G in DFNA5 gene, which was faithfully cosegregated with hearing loss in the family.

Conclusion and significance

The missense mutation in intron 7 of DFNA5 causes skipping of exon 8, resulting in premature termination of the open reading frame. This type of mutation has repeatedly confirmed that it provides more evidence for the previous view and provides a more solid foundation for future research.

Chinese Abstract

背景：迄今为止, 全球范围内, 已报告在常染色体显性遗传非综合征性听力损失的家庭中出现5 个 DFNA5 突变。所有的突变都会导致 mRNA 水平的外显子 8 跳跃, 这导致蛋白质被截断, 并且蛋白质可以导致耳毒性功能获得。

目的：在本研究中, 我们发现了一个跨越四代、43名成员的常染色体显性非综合征性听力损失的中国族系。我们要找出原因基因和突变。

方法：应用微卫星标记在DFNA 23位点初步筛选25个基因, 通过连锁分析对数据进行分析。

结果：我们应用 8 个微卫星标记, 将基因座映射到 D7S629 和 D7S516 之间的区域（两点 lod-评分 5.39)。通过对作图区域候选基因的直接测序, 我们在DFNA5基因中发现了一个新的错义突变ivs7-2 A > G, 该突变忠实地伴随着家族听力损失一起出现。

结论及意义：DFNA5内含子7错义突变导致外显子8跳跃, 导致可译框架提前终止。这种类型的突变反复证实了它为之前的观点提供了更多的证据, 为未来的研究提供了更坚实的基础。

Keywords:

• DFNA5
• hearing loss
• linkage analysis
• mutation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Key projects of the National Natural Science Foundation of China [81530031]; National major scientific research plan of China [2013CB945402]; Military Medical Science and Technology Youth Cultivation Project [14QNP067].