title: Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner.
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 impaired. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females. 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 beta (TGFbeta) superfamily and is specifically expressed in oocytes, its function is unknown. 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.
authors.affiliation: AgResearch Molecular Biology Unit, and Centre for Gene Research, Department of Biochemistry, University of Otago, Dunedin, New Zealand. galloways@agresearch.cri.nz
authors.forename: S M
authors.initials: SM
authors.lastname: Galloway
authors.forename: K P
authors.initials: KP
authors.lastname: McNatty
authors.forename: L M
authors.initials: LM
authors.lastname: Cambridge
authors.forename: M P
authors.initials: MP
authors.lastname: Laitinen
authors.forename: J L
authors.initials: JL
authors.lastname: Juengel
authors.forename: T S
authors.initials: TS
authors.lastname: Jokiranta
authors.forename: R J
authors.initials: RJ
authors.lastname: McLaren
authors.forename: K
authors.initials: K
authors.lastname: Luiro
authors.forename: K G
authors.initials: KG
authors.lastname: Dodds
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: A E
authors.initials: AE
authors.lastname: Beattie
authors.forename: G H
authors.initials: GH
authors.lastname: Davis
authors.forename: O
authors.initials: O
authors.lastname: Ritvos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D018076:DNA, Complementary; D005260:Female; D055429:Growth Differentiation Factor 9; D006133:Growth Substances / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007247:Infertility, Female / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010060:Ovulation / Q000502:physiology*; D010375:Pedigree; D011487:Protein Conformation; D012756:Sheep; D014960:X Chromosome
chemical_list: C525901:BMP15 protein, human; C525902:Bmp15 protein, mouse; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; C525897:GDF9 protein, human; C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins