Association of Genetic Variants in the TMCO1 Gene with Clinical Parameters Related to Glaucoma and Characterization of the Protein in the Eye
Association of Genetic Variants in the TMCO1 Gene with Clinical Parameters Related to Glaucoma and Characterization of the Protein in the Eye
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DOI：
10.1167/iovs.11-9047
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发表时间：
2012-07-01
影响因子：
4.4
通讯作者：
Craig, Jamie E.
中科院分区：
文献类型：
--
作者：
Sharma, Shiwani;Burdon, Kathryn P.;Craig, Jamie E.
目的。青光眼是全世界不可逆转失明的主要原因。原发性开角型青光眼（POAG）是最常见的亚型。我们最近报道了染色体位点 1q24 和 9p21 的遗传变异与 POAG 的关联。在本研究中，我们确定了 TMCO1 基因附近 1q24 处最显着相关的单核苷酸多态性 (SNP) rs4656461 与青光眼风险和诊断相关临床参数的关联，并确定了人类 TMCO1 蛋白的眼部表达和亚细胞定位，以了解其参与 POAG 的机制。使用线性回归在 1420 个 POAG 病例中评估了 SNP rs4656461 与五个临床参数的关联。对 95 例具有明显家族史和晚期疾病的病例进行了 TMCO1 基因突变筛查。通过免疫标记和 GFP 融合来确定 TMCO1 蛋白的眼部表达和亚细胞定位。结果。数据表明，rs4656461 风险等位基因 (GG) 纯合子的个体在诊断时比该等位基因非携带者年轻 4 至 5 岁。我们的数据表明 TMCO1 蛋白在人眼的大多数组织中表达，包括小梁网和视网膜。然而，亚细胞定位与其他研究中报道的不同。我们证明内源蛋白在体内和离体定位于细胞质和细胞核。在细胞核中，蛋白质定位于核仁。结论。这项研究显示了 TMCO1 及其周围的遗传变异与 POAG 诊断时年龄之间的关系，并为该基因的潜在细胞功能提供了线索。 （投资眼科可见科学。2012 年；53：4917-4925）DOI：10.1167/iovs.11-9047
PURPOSE. Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG.METHODS. Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion.RESULTS. The data suggest that individuals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli.CONCLUSIONS. This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene. (Invest Ophthalmol Vis Sci. 2012;53:4917-4925) DOI:10.1167/iovs.11-9047