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.

Physiological effects of major genes affecting ovulation rate in sheep

“…In some instances, the differences in ovulation rate have been attributed to the action of a single or a closelylinked group of genes [4]. Indeed mutations with major effects on ovulation rate have been identified in two genes of the transforming growth factor beta (TGFβ) superfamily and a TGFβ receptor, namely bone morphogenetic protein (BMP15), growth differentiation factor 9b (GDF9) and BMP receptor-IB (ALK6) [10,11,23,28,33]. Further mutations in some of these genes or in different genes are likely to be present in other prolific breeds.…”

A presentation of the differences between the sheep and goat genetic maps

“…These are the Spider Lamb [6], Booroola [30], Callipyge [10] and Inverdale [12] traits in sheep, and the Polled Intersex trait in goats [21]. Many QTL regions have been identified for a vast range of traits from genome screens in sheep.…”

“…In the case of goats, the reason for developing a genetic map was to map the locus responsible for the Polled Intersex Syndrome [26], and relatively little genetic map development has occurred for goats since this locus was mapped. Initially, much of the work on the sheep genetic map was aimed at identifying loci responsible for fertility traits such as Inverdale and Booroola [12,20]. More recently mapping efforts in sheep have also included searches for traits affecting meat, wool, and disease susceptibility and resistance [4,5,8,15].…”

“…This focus on mapping specific traits has lead to genetics maps that have uneven distributions of markers on chromosomes. Not surprisingly, regions disproportionately rich in markers are found in areas of the maps that are near traits of interest, e.g., chromosome 6 with Booroola and Spider Lamb Syndrome, chromosome 18 and callipyge/Carwell, and the X chromosome and Inverdale in sheep; and chromosome 1 with Polled Intersex Syndrome in goats [6,12,21,29,30]. More recently development of the sheep genetic map has focused on increasing the number of mapped markers that are associated with genes so as to increase the number of links to maps of other species such as humans and mice [18].…”

Mouse models for identifying genes modulating fertility parameters

“…Other species than mice also helped in the identification of new genes involved in folliculogenesis. This is the case of the sheep model in which different kinds of mutations in FecX (Bmp15) (Galloway et al, 2000) and BmpR1B (Mulsant et al, 2001) displayed variable phenotypes from total infertility to superfertility in terms of ovulation rate. Furthermore, several important genes for female fertility are located on the X chromosome (for a review, see Vaiman, 2002).…”