Tosh Durgadatta, Rani Hanumanth Surekha, Murty Upadhyayula Suryanarayana, Deenadayal Anupama, Grover Paramjit
From the 1Biology Division, CSIR Indian Institute of Chemical Technology, Hyderabad, India; 2Department of Genetics, Osmania University, Hyderabad, India; and 3Infertility Institute and Research Center, Secunderabad, India.
Menopause. 2015 May;22(5):520-6. doi: 10.1097/GME.0000000000000340.
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.
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.
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.
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.
我们研究的目的是确定在印度人群中，生殖系α因子（FIGLA）基因变异与卵巢早衰（POF）之间的关联。
本研究招募了219例特发性POF女性患者和230例健康对照。通过聚合酶链反应和测序分析FIGLA基因的所有外显子、内含子-外显子边界和非翻译区。使用PolyPhen、SIFT、MutationTaster、PMUT、I-Mutant、Mupro、Align-GVGD、PROVEAN和HOPE软件对所有FIGLA变异进行计算机模拟分析，以预测其致病性和蛋白质稳定性的变化。
在POF女性患者中检测到7种不同的FIGLA变异。外显子3的两种变异，即c.427G→C和c.557C→T，在病例组和对照组之间显示出强关联（分别为P = 0.02和P = 0.02）。在基因型和显性模型中，病例组和对照组在这两种变异上均观察到显著差异。单倍型分析未发现对照组与POF女性之间存在显著差异。仅在POF病例中发现一个非同义变异p.(Arg83Cys)。变异p.(Arg83Cys)位于FIGLA基因的功能域（碱性螺旋-环-螺旋）中，蛋白质比对显示其在哺乳动物中高度保守。计算机模拟分析表明p.(Arg83Cys)和p.(Ser141Thr)变异在POF发病机制中具有功能作用。
我们已证实印度女性中FIGLA基因变异与POF之间存在强关联，这可能是特发性POF发生发展的一个潜在遗传危险因素。然而，需要进一步的独立遗传和功能研究来证实我们的发现。
