Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure.

Objective: The aim of our study was to identify the association of FIGLA (factor in the germ line α) gene variants with premature ovarian failure (POF) in the Indian population.

Methods: Two hundred nineteen women with idiopathic POF and 230 healthy controls were recruited for this study. All exons, intron-exon boundaries, and untranslated regions of the FIGLA gene were analyzed by polymerase chain reaction and sequencing. All FIGLA variants were analyzed in silico, using PolyPhen, SIFT, MutationTaster, PMUT, I-Mutant, Mupro, Align-GVGD, PROVEAN, and HOPE software, to predict pathogenicity and changes in protein stability.

Results: Seven different FIGLA variants were detected among women with POF. Two exon 3 variants, c.427G → C and c.557C → T, showed strong association between cases and controls (P = 0.02 and P = 0.02, respectively). Significant differences in both of these variants were observed between cases and controls in genotype and dominant models. No significant difference between controls and women with POF was found on haplotype analysis. A nonsynonymous variant, p.(Arg83Cys), was found only in POF cases. Variant p.(Arg83Cys) lies in the functional domain of the FIGLA gene (basic helix-loop-helix), and protein alignments reveal that it is highly conserved among mammals. In silico analysis suggests the functional involvement of p.(Arg83Cys) and p.(Ser141Thr) variants in POF pathogenesis.

Conclusions: We have established a strong association between FIGLA gene variants and POF in Indian women, which may be a potential genetic risk factor in the development of idiopathic POF. However, further independent genetic and functional studies are necessary to confirm our findings.