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Submitted on June 8, 2006
Accepted on October 5, 2006
INRA, Station d'Amélioration Génétique des Animaux, BP 52627, 31326 Castanet-Tolosan, France; Department of Medical Sciences, University of Milan, Lab of Experimental Endocrinology, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, 20095 Cusano Milanino (MI), Italy; INRA, Physiologie de la Reproduction et des Comportements, UMR 6175 INRA-CNRS-Université de Tours-Haras Nationaux, 37380 Nouzilly, France; INRA, Laboratoire de Génétique Cellulaire, BP 52627, 31326 Castanet-Tolosan, France
* To whom correspondence should be addressed. 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 transforming growth factor (TGFbeta) superfamily pathway : the bone morphogenetic protein 15 (BMP15, also known as GDF9b), growth differentiation factor 9 (GDF9) and BMP receptor type IB (BMPRIB also known as ALK6). 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 BMPRIB 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 non-conservative 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 in the control of ovulation rate in sheep.
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