In-Silico Investigation of Effects of Single-Nucleotide Polymorphisms in PCOS-Associated CYP11A1 Gene on Mutated Proteins

Abstract

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.

Exploring the role of CDCA4 in liver hepatocellular carcinoma using bioinformatics analysis and experiments

“…The continued integration of bioinformatics in genetic research will undoubtedly catalyze future discoveries, providing deeper understanding of genetic mechanisms and paving the way for novel therapeutic strategies. [18][19][20][21][22][23] Investigating the expression of CDCA4 and its prognostic value in liver cancer is the aim of this investigation, along with its influence on the immune microenvironment. Through this investigation, we aim to elucidate the associations between CDCA4 and potential targets or signaling pathways pertinent to the onset and progression of liver cancer.…”

“…The continued integration of bioinformatics in genetic research will undoubtedly catalyze future discoveries, providing deeper understanding of genetic mechanisms and paving the way for novel therapeutic strategies. [18–23]…”

Exploring the association of ESR1 and ESR2 gene SNPs with polycystic ovary syndrome in human females: a comprehensive association study

“…One of the main concerns for most human females is the infertility associated with PCOS due to anovulatory or oligoovulatory infertility and menstrual irregularities. Even after conception many human females are more prone to miscarriage due to this condition [ 1 – 3 ]. Systemic complications include a higher risk of cardiovascular disease, dyslipidemia and hypertension, insulin resistance and a four-fold increased risk of developing Type 2 diabetes.…”

“…The PCOS associated genes can be classified into six categories: genes associated with adrenal and ovarian steroidogenesis, including cytochrome P450, family 11, sub-family A, member 1 (CYP11A1), cytochrome P450, family 17 (CYP17), cytochrome P450, family 19 (CYP19) and cytochrome P450, family 21 (CYP21); genes associated with the effects of steroid hormones such as androgen receptor gene (AR) and sex hormone binding globular protein (SHBG); genes regulating gonadotropin activity and regulation such as luteinizing hormone (LH), follicle stimulating hormone receptor (FSHR) and anti-mullerian hormone (AMH); genes linked to the activity and release of insulin such as calpain 10 (CAPN10), insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2) and insulin (INS) etc. [ 3 , 7 – 10 ]. Additionally Environmental factors that contribute to PCOS such as environmental endocrine disruptors (EEDs), obesity, and diet, have not been extensively documented [ 11 ].…”