A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age-related cataracts
A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age-related cataracts
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NEIL2 3-UTR 中 microRNA 结合位点的变异导致对年龄相关性白内障的易感性
DOI：
10.1096/fj.201802291r
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Guan, Huaijin
中科院分区：
文献类型：
--
作者：
Kang, Lihua;Zou, Xi;Guan, Huaijin
透镜细胞中的DNA损伤被认为是年龄相关性白内障（ARC）发病的关键触发因素。在DNA修复途径中，碱基切除修复（BER）途径负责修复DNA中的单链断裂。在这项病例对照研究中，993例ARC病例和993名健康对照，我们对6个BER通路基因的microRNA（miRNA）区域内的9个单核苷酸多态性（SNP）进行了基因分型，并研究了它们与ARC易感性的相关性。我们鉴定了Nei样DNA糖基化酶2（NEIL 2）基因中的rs 4639：T > C与ARC显著相关。携带不同rs 4639等位基因的个体在ARC病例和对照的透镜囊组织中具有不同的NEIL 2表达。生物信息学预测rs 4639 T等位基因可破坏hsa-miR-3912- 5 p结合。荧光素酶报告基因测定的结果与该预测一致。本研究进一步证明了SNP修饰的miRNA对转录后基因的调控可能是ARC的一种潜在致病机制。可能影响BER途径基因的3 ' UTR的miRNA结合的SNP可能有助于差异疾病易感性。NEIL 2-rs 4639 T与ARC中的保护作用密切相关。这种保护作用可能是通过维持NEIL 2的正常表达来介导rs 4639 T与hsa-miR-3912- 5 p的破坏结合来实现的。需要进一步研究以产生具有NEIL 2变体的模型系统（细胞系或动物模型）。结果提供了2种分子靶标（例如，NEIL 2和hsa-miR-3912- 5 p）用于未来ARC的干预策略。康湖，加-地邹，X.，张，G.，向，J，王玉，杨，M.，陈旭，吴，J.，关氏H. NEIL 2 3 ' UTR中microRNA结合位点的变异赋予年龄相关性白内障的易感性
DNA damage in lens cells is considered a critical trigger for the onset of age-related cataracts (ARCs). Among DNA repair pathways, the base excision repair (BER) pathway is responsible for mending single-strand breaks in DNA. In this case-control study with 993 ARC cases and 993 healthy controls, we genotyped 9 single-nucleotide polymorphisms (SNPs) within microRNA (miRNA) regions of 6 BER pathway genes and examined their associations with ARC susceptibility. We identified rs4639:T > C in the Nei-like DNA glycosylase 2 (NEIL2) gene as significantly associated with ARCs. Individuals carrying different rs4639 alleles had distinct NEIL2 expression in lens capsule tissues from ARC cases and controls. Bioinformatics predicts that the rs4639 T allele could disrupt hsa-miR-3912-5p binding. The results of the luciferase reporter assay were in concordance with this prediction. This study has added more evidence that SNP-modified posttranscriptional gene regulation by miRNA might be a potential pathogenic mechanism of ARCs. SNPs potentially affecting miRNA binding to the 3 ' UTR of BER pathway genes could contribute to discrepant disease susceptibility. NEIL2-rs4639T was strongly associated with a protective role in ARCs. This protective role might be fulfilled by maintaining normal expression of NEIL2 in the mediation of disrupted binding of rs4639T with hsa-miR-3912-5p. A further study to generate model systems (cell lines or animal models) with NEIL2 variants is warranted. The results provide 2 molecular targets (e.g., NEIL2 and hsa-miR-3912-5p) for intervention strategies of ARC in the future.-Kang, L., Zou, X., Zhang, G., Xiang, J., Wang, Y., Yang, M., Chen, X., Wu, J., Guan, H. A variant in a microRNA binding site in NEIL2 3 ' UTR confers susceptibility to age-related cataract.