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
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
复制标题
DOI：
10.1210/en.2006-0764
复制
发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Mulsant, Philippe
中科院分区：
文献类型：
--
作者：
Bodin, Loys;Di Pasquale, Elisa;Mulsant, Philippe
最近在属于TGF β超家族途径的三个基因中发现了对绵羊排卵率和产仔数有重大影响的基因突变：骨形态发生蛋白15（BMP 15，也称为GDF9b），生长分化因子9（GDF9）和BMP受体IB型（也称为激活素样激酶6）。纯合子BMP 15或GDF 9突变由于正常卵泡发育失败而提高雌性不育，而BMP 15或GDF 9的杂合子动物以及BMP受体IB型的杂合子和纯合子动物显示出增加的排卵率。在目前的工作中，一个新的自然发生的突变BMP 15基因在高产量的Lacaune绵羊品种的描述。鉴定的变体是C53 Y错义非保守取代，导致蛋白质成熟肽中半胱氨酸与酪氨酸的氨基酸变化。至于在同一基因中发现的其他突变，这分别与杂合子和纯合子动物的排卵率和不育率增加有关。进一步的体外研究表明，C53 Y突变导致BMP 15蛋白的成熟过程受损，导致前体和成熟肽的分泌缺陷。总之，我们的研究结果证实了BMP 15因子在绵羊卵泡发生和排卵率控制中的重要作用。
Genetic mutations with major effects on ovulation rate and litter size in sheep were recently identified in three genes belonging to the TGF beta 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 amino-acidic 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.