Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene
Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene
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DOI：
10.1086/422103
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发表时间：
2004-07-01
影响因子：
9.8
通讯作者：
Persani, L
中科院分区：
文献类型：
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作者：
Di Pasquale, E;Beck-Peccoz, P;Persani, L
高促性腺激素性卵巢功能衰竭是女性不孕的常见原因。它是一种异质性疾病，在最严重的形式中，是卵巢发育不全（OD）的结果。大多数OD病例与主要的X染色体异常有关，但在核型正常的患者中，这种疾病的发病机制在很大程度上仍不明确。动物模型显示，位于人类Xp11.2的基因产物（BMP 15）在女性生殖中发挥着重要作用。BMP 15是卵母细胞特异性生长/分化因子，其刺激卵泡发生和颗粒细胞（GC）生长。我们报告两个姐妹篇与正常核型谁是受高促性腺激素卵巢功能衰竭由于OD。家族性表现提示了遗传起源，并筛选了候选基因的突变。一个杂合的非保守性取代前区的BMP 15（Y235 C）被确定在这两个姐妹篇，但不是在210个控制等位基因。这种突变是遗传自父亲的。突变体BMP 15似乎被异常加工，与GC生长减少相关，并拮抗野生型蛋白对GC增殖的刺激活性。总之，人类BMP 15中的第一个天然突变与家族性OD相关，表明BMP 15的作用是人类卵泡发生进展所必需的。这种情况代表了X连锁人类疾病的一个特殊例子，该疾病专门影响杂合女性，这些女性从未受影响的父亲那里继承了遗传改变。BMP 15缺陷参与人类高促性腺激素卵巢衰竭的发病机制。
Hypergonadotropic ovarian failure is a common cause of female infertility. It is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis (OD). Most OD cases are associated with major X-chromosome abnormalities, but the pathogenesis of this disorder is still largely undefined in patients with a normal karyotype. Animal models showed the important role in female reproduction played by the product of a gene located at Xp11.2 in humans (BMP15). BMP15 is an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. We report two sisters with a normal karyotype who are affected with hypergonadotropic ovarian failure due to OD. The familial presentation suggested a genetic origin, and candidate genes were screened for mutations. A heterozygous nonconservative substitution in the pro region of BMP15 (Y235C) was identified in both sisters but not in 210 control alleles. This mutation was inherited from the father. Mutant BMP15 appears to be processed abnormally, is associated with reduced GC growth, and antagonizes the stimulatory activity of wild-type protein on GC proliferation. In conclusion, the first natural mutation in human BMP15 is associated with familial OD, indicating that the action of BMP15 is required for the progression of human folliculogenesis. This condition represents an exceptional example of X-linked human disease exclusively affecting heterozygous females who inherited the genetic alteration from the unaffected father. BMP15 defects are involved in the pathogenesis of hypergonadotropic ovarian failure in humans.