School of Biochemistry and Biotechnology, University of Punjab, Lahore, 52254, Pakistan.
Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11451, Saudi Arabia.
J Ovarian Res. 2024 Jan 29;17(1):27. doi: 10.1186/s13048-023-01335-7.
Polycystic Ovary Syndrome (PCOS) affects a significant proportion of human females worldwide and is characterized by hormonal, metabolic, and reproductive dysfunctions, including infertility, irregular menstrual cycles, acanthosis nigricans, and hirsutism. Mutations in the estrogen receptor genes ESR1 and ESR2, involved in normal follicular development and ovulation, can contribute to development of the PCOS. The present study focuses on investigating the potential correlation between single nucleotide polymorphisms (SNPs) of ESR1 and ESR2 genes and the incidence of this syndrome.
For this study, SNPs in ESR1 and ESR2 genes were retrieved from the ENSEMBL database and analyzed for their effect on mutated proteins using different bioinformatics tools including SIFT, PolyPhen, CADD, REVEL, MetaLR, I-Mutant, CELLO2GO, ProtParam, SOPMA, SWISS-MODEL and HDDOCK.
All the SNPs documented in the present study were deleterious. All the SNPs except rs1583384537, rs1450198518, and rs78255744 decreased protein stability. Two variants rs1463893698 and rs766843910 in the ESR2 gene altered the localization of mutated proteins i.e. in addition to the nucleus, proteins were also found in mitochondria and extracellular, respectively. SNPs rs104893956 in ESR1 and rs140630557, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene significantly changed the secondary structure of proteins (2D). SNPs that markedly changed 3D configuration included rs1554259481, rs188957694 and rs755667747 in ESR1 gene and rs1463893698, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene. Variants rs1467954450 (ESR1) and rs140630557 (ESR2) were identified to reduce the binding tendency of ESRα and β receptors with estradiol as reflected by the docking scores i.e. -164.97 and -173.23, respectively.
Due to the significant impact on the encoded proteins, these variants might be proposed as biomarkers to predict the likelihood of developing PCOS in the future and for diagnostic purposes.
多囊卵巢综合征（PCOS）影响着全球相当一部分女性，其特征为激素、代谢和生殖功能紊乱，包括不孕、月经不规律、黑棘皮病和多毛症。雌激素受体基因 ESR1 和 ESR2 的突变与正常卵泡发育和排卵有关，可能导致 PCOS 的发生。本研究重点探讨了 ESR1 和 ESR2 基因的单核苷酸多态性（SNP）与该综合征发病之间的潜在相关性。
本研究从 ENSEMBL 数据库中检索了 ESR1 和 ESR2 基因的 SNP，并使用不同的生物信息学工具（包括 SIFT、PolyPhen、CADD、REVEL、MetaLR、I-Mutant、CELLO2GO、ProtParam、SOPMA、SWISS-MODEL 和 HDDOCK）分析它们对突变蛋白的影响。
本研究中记录的所有 SNP 均为有害 SNP。除 rs1583384537、rs1450198518 和 rs78255744 外，所有 SNP 均降低了蛋白稳定性。ESR2 基因中的两个变体 rs1463893698 和 rs766843910 改变了突变蛋白的定位，即除了细胞核，蛋白质还分别存在于线粒体和细胞外。ESR1 基因中的 rs104893956 和 rs140630557、rs140630557、rs1596423459、rs766843910、rs1596405923、rs762454979 和 rs1384121511，ESR2 基因中的 rs1463893698、rs140630557、rs1596423459、rs766843910、rs1596405923、rs762454979 和 rs1384121511 显著改变了蛋白质的二级结构（2D）。明显改变 3D 结构的 SNP 包括 rs1554259481、rs188957694 和 rs755667747（ESR1 基因）以及 rs1463893698、rs140630557、rs1596423459、rs766843910、rs1596405923、rs762454979 和 rs1384121511（ESR2 基因）。变体 rs1467954450（ESR1）和 rs140630557（ESR2）被鉴定为降低 ESRα和β受体与雌二醇的结合倾向，反映在对接评分中分别为-164.97 和-173.23。
由于这些变体对编码蛋白有显著影响，因此它们可能被提议作为预测未来发生 PCOS 的可能性和用于诊断目的的生物标志物。
