Nature Genetics
25, 279 - 283 (2000)
doi:10.1038/77033
Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive mannerSusan M. Galloway1, Kenneth P. McNatty2, Lisa M. Cambridge1, Mika P.E. Laitinen3, Jennifer L. Juengel2, T. Sakari Jokiranta3, Robert J. McLaren1, Kaisu Luiro3, Ken G. Dodds4, Grant W. Montgomery1, Anne E. Beattie4, George H. Davis4
& Olli Ritvos31
AgResearch Molecular Biology Unit, and Centre for Gene Research, Department of Biochemistry, University of Otago, Dunedin, New Zealand. 2
AgResearch, Wallaceville Animal Research Centre, Upper Hutt, New Zealand. 3
Programme of Developmental and Reproductive Biology, Biomedicum Helsinki, and Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Finland. 4
AgResearch, Invermay Agricultural Centre, Mosgiel, New Zealand.
Correspondence should be addressed to Susan M. Galloway galloways@agresearch.cri.nzMultiple 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 (FecXI) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecXI/FecX+; ref. 1), but primary ovarian failure in homozygotes (FecXI/FecXI; ref. 2). Germ-cell development, formation of the follicle and the earliest stages of follicular growth are normal in FecXI/FecXI sheep, but follicular development beyond the primary stage is impaired3,
4. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype5 (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females6. We report here that the FecXI 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  (TGF) superfamily and is specifically expressed in oocytes, its function is unknown7,
8,
9. We show that independent germline point mutations exist in FecXI and FecXH 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.
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