School of Biochemistry and Biotechnology, University of Punjab, Lahore 52254, Pakistan.
Obstetrics and Gynaecology Department, Faculty of Medicine (FM), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Genes (Basel). 2022 Jul 12;13(7):1231. doi: 10.3390/genes13071231.
Polycystic ovary syndrome (PCOS) is a reproductive disorder with multiple etiologies, mainly characterized by the excess production of androgens. It is equally contributed to by genes and environment. The CYP11A1 gene is imperative for steroidogenesis, so any dysregulation or mutation in this gene can lead to PCOS pathogenesis. Therefore, nucleotide diversity in this gene can be helpful in spotting the likelihood of developing PCOS. The present study was initiated to investigate the effect of single nucleotide polymorphisms in human CYP11A1 gene on different attributes of encoded mutated proteins, i.e., sub-cellular localization, ontology, half-life, isoelectric point, instability index, aliphatic index, extinction coefficient, 3-D and 2-D structures, and transmembrane topology. For this purpose, initially coding sequence (CDS) and single nucleotide polymorphisms (SNPs) were retrieved for the desired gene from Ensembl followed by translation of CDS using EXPASY tool. The protein sequence obtained was subjected to different tools including CELLO2GO, ProtParam, PHYRE2, I-Mutant, SIFT, and PolyPhen. It was found that out of seventy-eight SNPs analyzed in this project, seventeen mutations, i.e., rs750026801 in exon 1, rs776056840, rs779154292 and rs1217014229 in exon 2, rs549043326 in exon 3, rs755186597 in exon 4, rs1224774813, rs757299093 and rs1555425667 in exon 5, rs1454328072 in exon 7, rs762412759 and rs755975808 in exon 8, and rs754610565, rs779413653, rs765916701, rs1368450780, and rs747901197 in exon 9 considerably altered the structure, sub-cellular localization, and physicochemical characteristics of mutated proteins. Among the fifty-nine missense SNPs documented in present study, fifty-five and fifty-three were found to be deleterious according to SIFT and PolyPhen tools, respectively. Forty-nine missense mutations were analyzed to have a decreasing effect on the stability of mutant proteins. Hence, these genetic variants can serve as potential biomarkers in human females for determining the probability of being predisposed to PCOS.
多囊卵巢综合征（PCOS）是一种具有多种病因的生殖障碍疾病，主要表现为雄激素的过度产生。它是由基因和环境共同作用引起的。CYP11A1 基因对类固醇的生物合成至关重要，因此该基因的任何调控失常或突变都可能导致 PCOS 的发病机制。因此，该基因中的核苷酸多样性有助于发现 PCOS 的发病可能性。本研究旨在探讨人类 CYP11A1 基因中单核苷酸多态性对编码突变蛋白不同属性的影响，即亚细胞定位、本体论、半衰期、等电点、不稳定性指数、脂肪指数、消光系数、3-D 和 2-D 结构以及跨膜拓扑结构。为此，首先从 Ensembl 中检索了所需基因的编码序列（CDS）和单核苷酸多态性（SNP），然后使用 EXPASY 工具翻译 CDS。获得的蛋白质序列使用包括 CELLO2GO、ProtParam、PHYRE2、I-Mutant、SIFT 和 PolyPhen 在内的不同工具进行分析。结果发现，在本项目分析的 78 个 SNP 中，有 17 个突变，即外显子 1 中的 rs750026801、外显子 2 中的 rs776056840、rs779154292 和 rs1217014229、外显子 3 中的 rs549043326、外显子 4 中的 rs755186597、外显子 5 中的 rs1224774813、rs757299093 和 rs1555425667、外显子 7 中的 rs1454328072、外显子 8 中的 rs762412759 和 rs755975808，以及外显子 9 中的 rs754610565、rs779413653、rs765916701、rs1368450780、和 rs747901197，极大地改变了突变蛋白的结构、亚细胞定位和理化特性。在本研究记录的 59 个错义 SNP 中，根据 SIFT 和 PolyPhen 工具，分别有 55 个和 53 个被认为是有害的。分析了 49 个错义突变，这些突变对突变蛋白的稳定性有降低作用。因此，这些遗传变异可以作为人类女性中潜在的生物标志物，用于确定其是否容易患上 PCOS。
