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

• Published in: Endocrinology (Philadelphia) 2007-01, Vol.148 (1), p.393-400
• Main Authors: Bodin, Loys, Di Pasquale, Elisa, Fabre, Stéphane, Bontoux, Martine, Monget, Philippe, Persani, Luca, Mulsant, Philippe
• Format: Article
• Language: English
• Subjects: Activin; Amino Acid Sequence; Animals; Biological and medical sciences; Birth control; Bone morphogenetic proteins; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - secretion; Consensus Sequence; Endocrinology and metabolism; Female; Folliculogenesis; Fundamental and applied biological sciences. Psychology; Growth Differentiation Factor 9; Gynecology. Andrology. Obstetrics; Heterozygote; Homozygote; Human health and pathology; Infertility - genetics; Infertility - pathology; Infertility - physiopathology; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - secretion; Kinases; Life Sciences; Litter size; Medical sciences; Molecular Sequence Data; Mutation; Ovarian Follicle - pathology; Ovarian Follicle - physiopathology; Ovaries; Ovulation; Ovulation - physiology; Peptides; Point Mutation; Proteins; Receptors; Secretion; Sheep; Sheep - genetics; Sheep Diseases - genetics; Sheep Diseases - pathology; Sheep Diseases - physiopathology; Sterility; Sterility. Assisted procreation; Tyrosine; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-0764

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