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

Nature Genetics volume 25, pages 279–283 (2000)Cite this article

Abstract

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 (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 β (TGFβ) 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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Figure 1: Linkage mapping of FecXI to the sheep X chromosome.
Figure 2: Sheep BMP15 sequence and mutations.
Figure 3: Homology-based molecular model of sheep BMP15 and FecXI mutated BMP15 protein molecules.
Figure 4: Ovary and oocyte specific expression of sheep BMP15.

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Acknowledgements

We thank D. Hill for initiating the sheep X-chromosome linkage mapping project; G. Bruce for management and recording of the Inverdale and Hanna flocks; A. Gray and M. Hanna for access to their flocks; and J. McEwan and P. Guilford for critical comments on the manuscript. This work was funded by the New Zealand Foundation for Research Science and Technology (S.G., K.M., L.C., J.J., R.M., K.D., G.M., A.B, G.D.), the Academy of Finland, the Jalmari and Rauha Ahokas Foundation and the Helsinki University Central Hospital Funds (M.L., T.S.J., K.L., O.R.).

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Authors and Affiliations

  1. Department of Biochemistry, AgResearch Molecular Biology Unit, and Centre for Gene Research, University of Otago, Dunedin, New Zealand

    Susan M. Galloway, Lisa M. Cambridge, Robert J. McLaren & Grant W. Montgomery

  2. AgResearch, Wallaceville Animal Research Centre, Upper Hutt, New Zealand

    Kenneth P. McNatty & Jennifer L. Juengel

  3. Programme of Developmental and Reproductive Biology, Biomedicum Helsinki,

    Mika P.E. Laitinen, T. Sakari Jokiranta, Kaisu Luiro & Olli Ritvos

  4. Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Finland

    Mika P.E. Laitinen, T. Sakari Jokiranta, Kaisu Luiro & Olli Ritvos

  5. AgResearch, Invermay Agricultural Centre, Mosgiel, New Zealand

    Ken G. Dodds, Anne E. Beattie & George H. Davis

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  1. Susan M. Galloway
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Correspondence to Susan M. Galloway.

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Galloway, S., McNatty, K., Cambridge, L. et al. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet 25, 279–283 (2000). https://doi.org/10.1038/77033

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