Abstract
Objective: Premature ovarian insufficiency (POI) is one of the most common reproductive endocrinological causes of infertility in women of child-bearing age. The purpose of this study was to identify FIGLA gene mutations in Chinese patients with POI and to investigate the underlying mechanism.Methods: A total of 113 patients with idiopathic POI and 100 healthy controls were recruited for the analysis of FIGLA variants. Based on the identification of common mutations in the FIGLA, wild-type and mutant plasmids were constructed and transfected into HEK293 cells. Luciferase reporter genes were used to determine the effect of wild-type and mutant FIGLA genotypes on the transcriptional activity of its downstream targets, the zona pellucida glycoprotein genes ZP1, ZP2, and ZP3. Chromatin immunoprecipitation was used to determine the level of binding between wild-type and mutant FIGLA with the ZP1, ZP2, and ZP3 promoters.Results: Three different FIGLA mutations were identified in four patients with POI. Two patients carried the mutation c.11C>A (p.A4E), and the other two patients, respectively, carried the mutations c.625G>A (p.V209I) and c.84C>A (p.D28E). The luciferase reporter assay indicated that ZP1, ZP2, and ZP3 transcriptional activities were significantly reduced in individuals with FIGLA mutations. Chromatin immunoprecipitation indicated that the FIGLA mutation significantly decreased binding with the ZP1, ZP2, and ZP3 promoters.Conclusion: FIGLA mutation affects gene transcriptional regulation of its downstream target genes ZP1, ZP2, and ZP3, highlighting a new candidate genetic factor that causes POI. Our study demonstrates that FIGLA has a regulatory effect on reproduction-specific genes, thereby providing a basis for elucidating the specific regulatory mechanism of FIGLA in germ cell growth and development.
Highlights
Premature ovarian insufficiency (POI) refers to nonphysiological amenorrhea due to ovarian failure in women before the age of 40
Among the 113 Chinese POI subjects, we identified three missense mutations in the FIGLA gene in four patients (Figure 1A): c.11C>A (p.A4E), c.84C>A (p.D28E), and c.625G>A (p.V209I), which have been already reported in the online dbSNP database
One POI patient (P9) carried a missense mutation c.625G>A, which caused a change in the amino acid at position 209 of the encoded protein from valine to isoleucine (p.V209I)
Summary
Premature ovarian insufficiency (POI) refers to nonphysiological amenorrhea due to ovarian failure in women before the age of 40. The incidence of POI is about 3.9% [3], and is a major factor leading to female infertility. The etiology of POI is complex, which includes hereditary, autoimmune, iatrogenic, infection, and environmental factors, and its pathogenic mechanism remains unclear. Hereditary factors such as chromosomal abnormalities and gene mutations [4] have long been regarded as the major pathogenic factors of POI. Primordial follicle formation is an important signal that establishes reproductive potential in women and is a key factor in determining whether POI or premature menopause develops. Several genes have been identified to play a potential role in the formation and development, including NOBOX, FIGLA, SOHLH1, LHX8, FOXO3, and other follicular development-specific transcription factors [5,6,7,8]
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