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 precisely regulate follicular development so that, normally, only one follicle is selected to ovulate. The Inverdale (FecX(I)) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecX(I)/FecX(+); ref. 1). but primary ovarian failure in homozygotes (FecX(I)/FecX(I); ref. 2). Germcell development, formation of the follicle and the earliest stages of follicular growth 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 Inverdale sheep also has the same X-linked phenotype(5) (Hanna, FecX(H)). Crossing FecX(I) with FecXH animals produces FecX(I)/FecX(H) infertile females phenotypically indistinguishable from FecX(I)/FecX(I) females(6). We report here that the FecX(I) locus maps to an orthologous chromosomal region syntenic to human Xp11.2-11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Whereas BMP15 is a member of the transforming growth factor beta (TGF beta) superfamily 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 female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.