Premature ovarian failure (POF) is a common cause of female infertility affecting about 12% of women under the age of 40. This heterogeneous disorder is characterized by primary or secondary amenorrhea and elevated gonadotropin values. Several defects can cause POF, including autoimmunity, X chromosome abnormalities and gene mutations, but its pathogenesis is still unknown in the vast majority of women with normal karyotype. We recently described two sisters affected with hypergonadotropic ovarian failure and primary amenorrhea that were carriers of a mutation in the gene encoding Bone Morphogenetic Protein 15 (BMP15) that was inherited from their father. This evidence is consistent with a critical role played by this oocyte-derived growth factor in the progression of folliculogenesis in humans, as previously shown in rodents and sheep. In this study we report the genetic analysis of BMP15 gene in 190 unrelated women with idiopathic POF: 25 cases with primary amenorrhea, 153 with secondary and 11 with intermittent POF. With the informed consent of patients, genetic screening was performed by dHLPC, using leukocyte DNA. Any identified variant was confirmed and characterized by automated sequencing. Our investigations showed the presence of 6 variants, the already reported Y235C mutation in one case and 5 new variants in 17 patients: one insertion (262insLeu) in 11 cases and four missense alterations (A180T in 5 cases, L148P, R68W and S5R in 1 case each). Except the 262insLeu, the other 4 variants were not found in the genomic DNA from 95 women who experienced the physiological menopause after 50 years of age and 150 controls from the general population. These novel variants were present in the heterozygous state in women with secondary amenorrhea.
In conclusion, these findings indicate the frequent association of BMP15 gene variants with the POF phenotype in humans (9/190 patients) and are consistent with the critical role played by BMP15 in human folliculogenesis.