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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

Institut National de la Recherche Agronomique, UR631, Station d’Amélioration Génétique des Animaux (L.B.), and UR444, Laboratoire de Génétique Cellulaire (P.Mu.), INRA, F-31326 Castanet-Tolosan, France; Department of Medical Sciences (E.D.P., L.P.), Laboratory of Experimental Endocrinology, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20095 Cusano Milanino, Italy; and Institut National de la Recherche Agronomique, UMR6175, Physiologie de la Reproduction et des Comportements (S.F., M.B., P.Mo.), INRA, F-37380 Nouzilly, France

Address all correspondence and requests for reprints to: Loys Bodin, Institut National de la Recherche Agronomique, Station d’Amélioration Génétique des Animaux, BP 52627, 31326 Castanet-Tolosan, France. E-mail: loys.bodin{at}toulouse.inra.fr.

Genetic mutations with major effects on ovulation rate and litter size in sheep were recently identified in three genes belonging to the TGFß 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.

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