背景:多囊卵巢综合征(PCOS)影响全球相当大比例的人类女性,其特征是激素,新陈代谢,和生殖功能障碍,包括不孕症,月经周期不规则,黑棘皮病,和多毛症。雌激素受体基因ESR1和ESR2的突变,参与正常卵泡发育和排卵,有助于PCOS的发展。本研究的重点是研究ESR1和ESR2基因的单核苷酸多态性(SNP)与该综合征的发生率之间的潜在相关性。
方法:对于本研究,从ENSEMBL数据库中检索ESR1和ESR2基因中的SNP,并使用包括SIFT在内的不同生物信息学工具分析其对突变蛋白的影响。PolyPhen,CADD,REVEL,MetaLR,I-Mutant,CELLO2GO,ProtParam,SOPMA,瑞士模型和HDDOCK。
结果:本研究中记录的所有SNP都是有害的。除rs1583384537、rs1450198518和rs78255744外,所有SNP均降低了卵白的稳固性。ESR2基因中的两个变体rs1463893698和rs766843910改变了突变蛋白的定位,即除了细胞核之外,在线粒体和细胞外也发现了蛋白质,分别。SNPsrs104893956中的ESR1和rs140630557、rs140630557、rs1596423459、rs766843910、rs1596405923、rs762454979和rs1384121511中的ESR2基因显著改变了蛋白质的二级结构(2D)。显著改变3D构型的SNP包括ESR1基因中的rs1554259481、rs188957694和rs755667747以及ESR2基因中的rs1463893698、rs140630557、rs1596423459、rs766843910、rs1596405923、rs762454979和rs1384121511。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趋势,如分别由对接分数即-164.97和-173.23反映的。
结论:由于对编码蛋白的显著影响,这些变异可能被提议作为生物标志物来预测未来发生PCOS的可能性,并用于诊断目的.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.