Mutations in DFNA5 lead to autosomal dominant non-syndromic sensorineural hearing loss that starts at the high frequencies. To date, only three DFNA5 mutations have been described, and although different at the genomic DNA level, all lead to exon 8 skipping at the mRNA level. This remarkable fact has led towards the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation and not by haplo-insufficiency as previously thought. Here, we describe a fourth DFNA5 mutation: the insertion of a cytosine at nucleotide position 640 (AF073308.1:_c.640insC, AAC69324.1:_p. Thr215HisfsX8). Unlike the previously described mutations, this frameshift mutation truncates the protein in exon 5 of the gene. Although the mutation was found in an extended Iranian family with hereditary hearing loss, it does not segregate with the hearing loss phenotype and is even present in persons with normal hearing. This fact provides further support for the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation.

中文翻译：

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新型DFNA5突变不会引起伊朗家庭的听力损失。

DFNA5中的突变导致常染色体显性遗传性非综合征性感觉神经性听力损失，该损失始于高频。迄今为止，仅描述了三个DFNA5突变，尽管在基因组DNA水平上有所不同，但所有突变均导致在mRNA水平上跳过外显子8。这一非凡的事实导致了这样一个假说，即与DFNA5相关的听力损失是由功能获得性突变引起的，而不是由以前认为的单倍功能不足引起的。在这里，我们描述了第四个DFNA5突变：胞嘧啶在640位核苷酸上的插入（AF073308.1：_c.640insC，AAC69324.1：_p。Thr215HisfsX8）。与先前描述的突变不同，此移码突变将基因外显子5中的蛋白质截短。尽管该突变是在一个遗传性听力损失的伊朗大家庭中发现的，它与听力损失表型没有区别，甚至存在于听力正常的人中。这一事实为DFNA5相关性听力损失是由功能获得性突变引起的这一假设提供了进一步的支持。