Exploring the functional and structural impacts of high-risk nsSNPs in human BMP15 and GDF9 genes associated with premature ovarian failure: an in silico approach

Premature ovarian failure (POF) is a complex reproductive disorder characterized by the early loss of ovarian function. Two closely related members of the transforming growth factor-β (TGF-β) superfamily, bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) have been implicated in its pathogenesis. In this study, we investigated the potential pathogenicity of 429 non-synonymous SNPs (nsSNPs) in GDF9 and 290 nsSNPs in BMP15 using an integrative bioinformatics approach. Multiple computational tools including SIFT, PolyPhen-2, PROVEAN, MutationAssessor, FATHMM, PhD-SNP, SNPs&GO, MutPred2, VEST-4, DDMut, INPS-3D, DDGun-3D and MAESTRO were employed to identify high-risk variants. As a result, three pathogenic variants in GDF9 (C382R, C419Y and L430S) and three in BMP15 (C291Y, C320G and C357R) were predicted to significantly reduce protein stability and function. Molecular dynamics simulation was performed to explore the structural alterations in GDF9 and BMP15 proteins induced by these variations. The MD results revealed that all the identified high-risk nsSNPs particularly C382R (GDF9) and C291Y (BMP15) triggered significant changes on the protein structure. The variants were found to less stable compared to the wild-type proteins which was associated with the increased local and overall flexibility, impaired hydrogen bond network and loss or distortion of β-sheet elements. These findings suggest a destabilizing effect that could lead to reduced structural integrity, impaired protein folding or functional deficiencies and ultimately contribute to the pathogenesis of these ovarian-related proteins.