Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.
Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.
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DOI：
10.1002/humu.9374
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发表时间：
2005-10-01
期刊：
影响因子：
3.9
通讯作者：
Leal, Suzanne M
中科院分区：
文献类型：
--
作者：
Santos, Regie Lyn P;Wajid, Muhammad;Leal, Suzanne M
虽然许多听力障碍基因已被确定，只有少数这些基因已在人口研究中筛选。在这项研究中，168个巴基斯坦家庭的常染色体隐性听力障碍，而不是由于GJB 2（Cx 26）基因突变进行了基因组扫描。进行了两点和多点参数连锁分析。12个家庭的两点或多点LOD得分为1.4或更高的跨膜耳蜗表达基因1（TMC 1）区域内，并进行了进一步的筛选与直接DNA测序。在7个家系中发现了5个新的pupidine功能性非同义序列变异体，c.830A>G（p.Y277C）、c.1114G> A（p.V372M）、c.1334G>A（p.R445H）、c.2004T>G（p.S668R）和c.2035G>A（p.E679K），但在234条巴基斯坦对照染色体中没有观察到。变异体c.830A>G（p.Y277C）、c.1114G>A（p.V372M）和c.1334G>A（p.R445H）发生在高度保守的区域，并被预测位于疏水跨膜结构域内，而非同义变异体c.2004T>G（p.S668R）和c.2035G>A（p.E679K）发生在非高度保守的细胞外区域。有证据表明，c.2004T>G（p.S668R）变异可能发生在磷酸化位点。一个家族具有已知的剪接位点突变c.536 -8T>A。在巴基斯坦人群中，TMC 1引起的非综合征性听力损伤的患病率为4.4%（95%CI：1.9，8.6%）。TMC 1蛋白可能在内毛细胞的K（+）通道中具有重要功能，这与鉴定序列变体的蛋白质结构域的假设结构一致。
Though many hearing impairment genes have been identified, only a few of these genes have been screened in population studies. For this study, 168 Pakistani families with autosomal recessive hearing impairment not due to mutations in the GJB2 (Cx26) gene underwent a genome scan. Two-point and multipoint parametric linkage analyses were carried out. Twelve families had two-point or multipoint LOD scores of 1.4 or greater within the transmembrane cochlear expressed gene 1 (TMC1) region and were subjected to further screening with direct DNA sequencing. Five novel putatively functional non-synonymous sequence variants, c.830A>G (p.Y277C), c.1114G>A (p.V372M), c.1334G>A (p.R445H), c.2004T>G (p.S668R), and c.2035G>A (p.E679K), were found to segregate within seven families, but were not observed in 234 Pakistani control chromosomes. The variants c.830A>G (p.Y277C), c.1114G>A (p.V372M), and c.1334G>A (p.R445H) occurred at highly conserved regions and were predicted to lie within hydrophobic transmembrane domains, while non-synonymous variants c.2004T>G (p.S668R) and c.2035G>A (p.E679K) occurred in extracellular regions that were not highly conserved. There is evidence that the c.2004T>G (p.S668R) variant may have occurred at a phosphorylation site. One family has the known splice site mutation c.536 -8T>A. The prevalence of non-syndromic hearing impairment due to TMC1 in this Pakistani population is 4.4% (95%CI: 1.9, 8.6%). The TMC1 protein might have an important function in K(+) channels of inner hair cells, which would be consistent with the hypothetical structure of protein domains in which sequence variants were identified.