Novel TMC1 structural and splice variants associated with congenital nonsyndromic deafness in a Sudanese pedigree.
Novel TMC1 structural and splice variants associated with congenital nonsyndromic deafness in a Sudanese pedigree.
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DOI：
10.1002/humu.9302
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发表时间：
2005-01-01
期刊：
影响因子：
3.9
通讯作者：
Horstmann, Rolf D
中科院分区：
文献类型：
--
作者：
Meyer, Christian G;Gasmelseed, Nagla M;Horstmann, Rolf D
跨膜通道样基因 1 (TMC1) 的突变已被证明可导致常染色体显性和隐性形式的先天性非综合征性耳聋，分别与基因座 DFNA36 和 DFNB7/B11 相关。在受明显隐性非综合征性耳聋影响的苏丹谱系中，我们使用覆盖耳聋基因座 DFNB1 - DFNB30 的标记进行了连锁分析。在标记位置 D9S1876 处获得了 3.08 的两点 LOD 评分，该位置位于 TMC1 基因 DFNB7/B11 的第一个内含子内。通过 TMC1 外显子 3-22 的 DNA 测序，我们鉴定了外显子 13 中的结构变异 c.1165C>T，导致终止密码子 p.Arg389X，以及剪接位点变异 c.19+5G>A，与耳聋表型独立分离。在 243 名不相关的苏丹聋哑人中，有 4 名也观察到了 c.1165C>T [p.Arg389X] 突变，但在 292 名正常听力对照者中未发现任何突变。 TMC1 突变导致苏丹耳聋的发现证实并扩展了之前关于 TMC1 在隐性非综合征性耳聋中的作用的报道，并表明导致耳聋的 TMC1 突变可能发生在各个种族群体中。
Mutations of the transmembrane channel-like gene 1 (TMC1) have been shown to cause autosomal dominant and recessive forms of congenital nonsyndromic deafness linked to the loci DFNA36 and DFNB7/B11, respectively. In a Sudanese pedigree affected by an apparently recessive form of nonsyndromic deafness, we performed a linkage analysis using markers covering the deafness loci DFNB1 - DFNB30. A two-point LOD score of 3.08 was obtained at marker position D9S1876, located within the first intron of the TMC1 gene at DFNB7/B11. By DNA sequencing of TMC1 exons 3-22, we identified the structural variant c.1165C>T in exon 13, leading to the stop codon p.Arg389X, and the splice-site variant c.19+5G>A, independently segregating with the deafness phenotype. The c.1165C>T [p.Arg389X] mutation was also observed in four out of 243 unrelated deaf Sudanese individuals, but none of the mutations was found among 292 normal hearing controls. The finding of TMC1 mutations contributing to deafness in Sudan confirms and extends previous reports on the role of TMC1 in recessive nonsyndromic deafness and shows that deafness-causing TMC1 mutations may occur in various ethnic groups.