Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner

Multiple ovulations are uncommon in humans, cattle and many breeds of sheep . Pituitary gonadotrophins and as yet unidentified ovarian factors precisel y regulate follicular development so that, normally, only one follicle is s elected to ovulate. The Inverdale (FecX(I)) sheep, however, carries a natur ally occurring X-linked mutation that causes increased ovulation rate and t win and triplet births in heterozygotes (FecX(I)/FecX(+); ref. 1). but prim ary ovarian failure in homozygotes (FecX(I)/FecX(I); ref. 2). Germcell deve lopment, formation of the follicle and the earliest stages of follicular gr owth are normal in FecX(I)/FecX(I) sheep, but follicular development beyond the primary stage is impaired(3,4). A second family unrelated to the Inver dale sheep also has the same X-linked phenotype(5) (Hanna, FecX(H)). Crossi ng FecX(I) with FecXH animals produces FecX(I)/FecX(H) infertile females ph enotypically indistinguishable from FecX(I)/FecX(I) females(6). We report h ere that the FecX(I) locus maps to an orthologous chromosomal region synten ic to human Xp11.2-11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Wherea s BMP15 is a member of the transforming growth factor beta (TGF beta) super family and is specifically expressed in oocytes, its function is unknown(7- 9). We show that independent germline point mutations exist in FecX(I) and FecX(H) carriers. These findings establish that BMP15 is essential for fema le fertility and that natural mutations in an ovary-derived factor can caus e both increased ovulation rate and infertility phenotypes in a dosage-sens itive manner.