Impact of Missense Variants on the Structure and Function of Polycystic Ovary Syndrome-Associated HSD17B1 Gene

HSD17B1 regulates estrogen availability in the ovary, and its dysregulation is linked to cyst formation in polycystic ovary syndrome. This study aimed to understand the role of missense variants in HSD17B1 dysfunction. Bioinformatic tools (sift, polyphen2, panther, snps & go, phd-snp, pmut, snap and revel score) were used to identify the deleterious missense variants of HSD17B1 gene. InterPro and Pfam tools were utilized to predict the functional domain of these deleterious variants, and its impact on structure and stability of HSD17B1 was analyzed by Hope, MutPred2, I-Mutant 2.0, and Mupro. Further, the AutoDock was used to determine the binding affinity of NADP to HSD17B1 protein. Finally, the HSD17B1 expression in clinical samples was analyzed using qRT-PCR. Of the 355 missense variants identified, five (rs202173252, rs149630844, rs146159533, rs200202791, and rs138503851) variants were deleterious, pocketed at the NADP binding domain and located at the conserved region of HSD17B1. Further, series of in silico prediction and molecular docking shows only the variant T191I (rs138503851) has an adverse effect on HSD17B1 function because of increased unfavorable bonds and non-interaction of adenine and nicotinamide of NADP to the Glycine94 and Leucine93 of HSD17B1. Additionally, a two-fold reduced expression of HSD17B1 in peripheral blood of PCOS subjects was observed, compared to healthy individuals. Overall, these results indicate that rs138503851 genetic variant of HSD17B1 may affect estrogen synthesis in PCOS. However, further clinical studies are warranted to validate the presence of rs138503851 genetic variant to identify the potential females who are predisposal to the development of PCOS.