Harvard Center for Reproductive Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, BHX 504, Boston, Massachusetts 02114, USA.
J Clin Endocrinol Metab. 2012 Sep;97(9):E1798-807. doi: 10.1210/jc.2012-1264. Epub 2012 Jun 28.
A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations.
The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR.
Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes.
The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes.
In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.
在单等位基因和双等位基因 GNRHR 突变的个体中，已经确定了广泛的 GnRH 缺乏表型。
本研究的目的是确定生殖表型严重程度与 GNRHR 中罕见序列变异的数量和功能严重程度之间的相关性。
863 名具有不同形式 GnRH 缺乏的先证者、46 名家庭成员和 422 名对照者筛查 GNRHR 突变。70 名携带突变的受试者（32 名患者和 38 名家庭成员）根据突变的功能严重程度（完全或部分丧失功能）和受影响等位基因的数量（单等位基因或双等位基因）分为四组（G1-G4），并将这些类别映射到他们的临床表型上。
先证者中杂合罕见序列变异的患病率明显高于对照者（P < 0.01）。在 G1-G3 组（杂合子受试者，突变的严重程度和数量逐渐降低）中，与遗传负荷相关的促性腺激素低下表型。相比之下，G4 组的受试者，只有单等位基因突变，表现出更多样化的临床表型。
在 GnRH 缺乏和 GNRHR 双等位基因突变的患者中，严重程度和剂量定义的遗传负担与临床表型相关。相比之下，对于具有单等位基因 GNRHR 突变的患者，这种相关性并不成立。综上所述，这些数据表明，尚未确定的遗传和/或环境因素可能与单突变 GNRHR 等位基因结合产生生殖表型。
