A Novel Mutation in the Bone Morphogenetic Protein 15 Gene Causing Defective Protein Secretion Is Associated with Both Increased Ovulation Rate and Sterility in Lacaune Sheep

Abstract

Genetic mutations with major effects on ovulation rate and litter size in sheep were recently identified in three genes belonging to the TGFbeta superfamily pathway: the bone morphogenetic protein 15 (BMP15, also known as GDF9b), growth differentiation factor 9 (GDF9), and BMP receptor type IB (also known as activin-like kinase 6). Homozygous BMP15 or GDF9 mutations raise female sterility due to a failure of normal ovarian follicle development, whereas heterozygous animals for BMP15 or GDF9 as well as heterozygous and homozygous animals for BMP receptor type IB show increased ovulation rates. In the present work, a new naturally occurring mutation in the BMP15 gene in the high prolific Lacaune sheep breed is described. The identified variant is a C53Y missense nonconservative substitution leading to the aminoacidic change of a cysteine with a tyrosine in the mature peptide of the protein. As for other mutations found in the same gene, this is associated with an increased ovulation rate and sterility in heterozygous and homozygous animals, respectively. Further in vitro studies showed that the C53Y mutation was responsible for the impairment of the maturation process of the BMP15 protein, resulting in a defective secretion of both the precursor and mature peptide. Overall, our findings confirm the essential role of the BMP15 factor in the ovarian folliculogenesis and control of ovulation rate in sheep.

Characterization of recombinant human growth differentiation factor-9 signaling in ovarian granulosa cells

“…Studies using mice (Dong et al 1996;Carabatsos et al 1998) and sheep (Galloway et al 2000;Juengel et al 2002;Hanrahan et al 2004;Bodin et al 2006;McNatty et al 2006) with inactivating mutations in the GDF9 gene or involving peptide immunizations for either GDF9 or GDF9B have revealed important roles for these oocyte growth factors in the stimulation of early follicular growth and fertility. However, little has been known about the role of GDF9 in regulating fertility in humans.…”

Using sheep lines with mutations in single genes to better understand ovarian function

“…At least six different mutations have been identified in the BMP15 gene (Galloway et al 2000, Bodin et al 2007, Martinez-Royo et al 2008, Monteagudo et al 2009, Lahoz et al 2011 wherein ewes heterozygous for the mutations have increased ovulation rates and those homozygous for the mutations are infertile. While all the mutations have similar general effects on fertility, there are subtle differences, as the increases in ovulation rate observed in the heterozygous animals (Table 1) vary from 35 to 100% (McNatty et al 2004).…”

Genes involved in human premature ovarian failure

“…All together, the data so far collected in different mammalian species indicate that the role of BMP15 may be more critical in mono-ovulating species (such as sheep and human) than in the poly-ovulating ones (mice). Experimental disruption of Bmp15 gene in mice causes a mild fertility defect limited to females (Yan et al 2001), whereas natural missense mutations in several strains of ewes cause a hyperprolificacy phenotype in the heterozygous state (increased litter size to three to five lambs per litter against one in wild type) and a female infertility with complete block of folliculogenesis in the homozygous state (FecX factors; Galloway et al 2000, Davis 2004, McNatty et al 2005, Bodin et al 2007. BMP15 maps to a locus on the short arm of X chromosome (Xp11.2) within a 'POF critical region' where several of the TS traits are located including ovarian failure .…”