Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston 02114, MA, USA.
Hum Mol Genet. 2012 Oct 1;21(19):4314-24. doi: 10.1093/hmg/dds264. Epub 2012 Jul 5.
Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.
先天性促性腺激素释放激素（GnRH）缺乏症表现为性成熟缺失或不完全，以及不孕。尽管该疾病表现出明显的基因座和等位基因异质性，其致病突变既罕见又具有个体特异性，但在来自不同地理和种族起源的 GnRH 缺乏症患者中，促动力蛋白受体 PROKR2 的 L173R 突变似乎异常普遍。为了追踪 PROKR2 L173R 的遗传祖先，对 22 名携带 L173R 的 GnRH 缺乏症患者及其 30 名一级亲属进行了单倍型图谱分析。使用单倍型衰减模型估计了突变的年龄。13 名受试者具有信息性，在所有受试者中，突变均存在于相同的约 123 kb 单倍型上，其人群频率≤10%。因此，PROKR2 L173R 代表一个起源于约 9000 年前的创始突变。携带 PROKR2 L173R 相关 GnRH 缺乏症的遗传是复杂的，携带者之间的外显率差异很大，受另一个 PROKR2 等位基因中的额外突变（隐性遗传）或另一个基因（双重性）的影响。这种古老创始突变对生殖造成损害的悖论性发现，对 PROKR2 L173R 相关 GnRH 缺乏症的遗传机制以及相关的进化选择过程具有有趣的启示，包括对生殖相关基因的突变携带者的潜在选择优势。
