Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss
Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss
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DOI：
10.1093/hmg/10.22.2501
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发表时间：
2001-10-15
影响因子：
3.5
通讯作者：
Lesperance, MM
中科院分区：
文献类型：
--
作者：
Bespalova, IN;Van Camp, G;Lesperance, MM
仅影响 2000 Hz 及以下频率的非综合征性低频感音神经性听力损失 (LFSNHL) 是一种不寻常的听力损失类型，它会随着时间的推移而恶化，但不会发展为严重耳聋。这种类型的 LFSNHL 可能与轻度耳鸣有关，但与眩晕无关。我们之前报道过两个常染色体显性 LFSNHL 家族与 4p16、DFNA6 和 DFNA14 上相邻但不重叠的位点相关。然而，进一步的研究表明，DFNA6家族中患有LFSNHL的个体发生了排除DFNA14候选区域的重组事件，实际上是一个表型，因此，DFNA6和DFNA14是等位基因。 LFSNHL 在遗传上似乎几乎是同质的，因为已知只有一个 LFSNHL 家族映射到不同的染色体 (DFNA1)。 DFNA6/14 关键区域包括 WFS1，这是导致 Wolfram 综合征的基因，Wolfram 综合征是一种常染色体隐性遗传疾病，其特征为糖尿病和视神经萎缩，通常还伴有耳聋。在此，我们报告了在 6 个 LFSNHL 家族中发现的 WFS1 基因中的 5 种不同的杂合错义突变（T699M、A716T、V779M、L829P、G831D）。在所有测试的 LFSNHL 家族中均发现了 WFS1 突变，其中 A716T 在两个家族中独立出现。除了在 1/336 对照染色体中发现的 V779M 之外，至少 220 条对照染色体中未发现任何突变。该频率与 Wolfram 综合征杂合子携带者的患病率估计为 0.3-1% 一致。据报道，此类携带者感音神经性听力损失的风险增加。因此，我们得出结论，WFS1 突变是 LFSNHL 的常见原因。
Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.