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<p>Polycystic ovary syndrome (PCOS) is an intractable endocrine disorder of ill-defined genetic determinants. This study used an integrative computational strategy to detect and define high-impact genetic variants from RNA-seq data from PCOS patient-derived cumulus granulosa cells (NCBI-SRA: SRP404612). Raw FASTQ files were quality-checked using FastQC and underwent Trimmomatic for adapter trimming and quality trimming. Processed reads were mapped to the hg38 reference genome with STAR aligner in two-pass mode and then variant calling using GATK (HaplotypeCaller). ANNOVAR annotated 69,407 genetic variants including 5,875 non-synonymous SNPs from resulting VCF files. Stringent filtering (SIFT &lt; 0.05, PolyPhen-2 &gt; 0.85, CADD &gt; 20, MutationTaster &gt; 0.9, FATHMM &lt; 0.05, PROVEAN ≤ -2.5) identified 28 rare variants (MAF &lt; 0.01 in East Asian populations), of which 9 had high evolutionary conservation (ConSurf score ≥ 8). Pathogenicity prediction by MutPred2 and PhD-SNP categorized PEPD (V376M) and ZNF572 (C221Y) as disease-causing mutations, confirmed by ΔΔG values obtained using DynaMut2 analysis. Molecular dynamics simulation (100ns) revealed that PEPD V376M enhances structural fluctuations and local instability, which should impair prolidase function in extracellular matrix remodeling. ZNF572 C221Y induced enhanced flexibility and reduced compactness of the zinc finger domain, possibly disrupting DNA binding. These findings propose mechanisms by which such variants lead to ovarian dysfunction in PCOS. These results provide mechanistic explanations for the contribution of these variants to PCOS dysfunction and present encouraging targets for future functional validation.</p>

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Decoding PCOS pathogenesis: deleterious mutations in PEPD and ZNF572 uncovered by transcriptomics and molecular dynamics

  • 期刊论文

  • 发表日期：

    2026年5月2日

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  • Harshini Senthilkumar,
  • Tamil Barathi Palanisamy,
  • Jeyakanthan Jeyaraman,
  • Chun-Jung Chen,
  • Mohanapriya Arumugam

摘要

Polycystic ovary syndrome (PCOS) is an intractable endocrine disorder of ill-defined genetic determinants. This study used an integrative computational strategy to detect and define high-impact genetic variants from RNA-seq data from PCOS patient-derived cumulus granulosa cells (NCBI-SRA: SRP404612). Raw FASTQ files were quality-checked using FastQC and underwent Trimmomatic for adapter trimming and quality trimming. Processed reads were mapped to the hg38 reference genome with STAR aligner in two-pass mode and then variant calling using GATK (HaplotypeCaller). ANNOVAR annotated 69,407 genetic variants including 5,875 non-synonymous SNPs from resulting VCF files. Stringent filtering (SIFT < 0.05, PolyPhen-2 > 0.85, CADD > 20, MutationTaster > 0.9, FATHMM < 0.05, PROVEAN ≤ -2.5) identified 28 rare variants (MAF < 0.01 in East Asian populations), of which 9 had high evolutionary conservation (ConSurf score ≥ 8). Pathogenicity prediction by MutPred2 and PhD-SNP categorized PEPD (V376M) and ZNF572 (C221Y) as disease-causing mutations, confirmed by ΔΔG values obtained using DynaMut2 analysis. Molecular dynamics simulation (100ns) revealed that PEPD V376M enhances structural fluctuations and local instability, which should impair prolidase function in extracellular matrix remodeling. ZNF572 C221Y induced enhanced flexibility and reduced compactness of the zinc finger domain, possibly disrupting DNA binding. These findings propose mechanisms by which such variants lead to ovarian dysfunction in PCOS. These results provide mechanistic explanations for the contribution of these variants to PCOS dysfunction and present encouraging targets for future functional validation.