Seminara Stephanie B, Messager Sophie, Chatzidaki Emmanouella E, Thresher Rosemary R, Acierno James S, Shagoury Jenna K, Bo-Abbas Yousef, Kuohung Wendy, Schwinof Kristine M, Hendrick Alan G, Zahn Dirk, Dixon John, Kaiser Ursula B, Slaugenhaupt Susan A, Gusella James F, O'Rahilly Stephen, Carlton Mark B L, Crowley William F, Aparicio Samuel A J R, Colledge William H
Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
N Engl J Med. 2003 Oct 23;349(17):1614-27. doi: 10.1056/NEJMoa035322.
Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty.
We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice.
Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus.
Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.
青春期是一个复杂的生物学过程，涉及性发育、线性生长加速和肾上腺成熟，当促性腺激素释放激素开始由下丘脑分泌时启动。我们在人类和小鼠中开展研究以确定决定青春期开始的遗传因素。
我们在人类和小鼠中使用了互补的遗传学方法。对一个近亲结婚家庭中缺乏青春期发育的成员（特发性低促性腺激素性性腺功能减退）进行了候选基因GPR54的突变检测，该基因编码一种G蛋白偶联受体。在体外检测野生型和突变型GPR54之间的功能差异。同时，构建了Gpr54基因缺陷小鼠模型并进行表型分析。评估了人类和小鼠对外源性促性腺激素释放激素的反应性。
索引家系中的患病患者GPR54基因存在L148S突变的纯合子，一名患有特发性低促性腺激素性性腺功能减退的无关先证者被确定有两个不同的突变，即R331X和X399R。用突变构建体对COS-7细胞进行体外转染显示肌醇磷酸的积累显著减少。与六名无GPR54基因突变的特发性低促性腺激素性性腺功能减退患者相比，携带复合杂合突变（R331X和X399R）的患者内源性促性腺激素释放激素分泌减弱，促性腺激素释放激素的剂量反应曲线左移。Gpr54基因缺陷小鼠表现为孤立性低促性腺激素性性腺功能减退（雄性小鼠睾丸小，雌性小鼠阴道开口延迟且卵泡成熟缺失），但它们对外源性促性腺激素和促性腺激素释放激素均有反应，且下丘脑促性腺激素释放激素水平正常。
G蛋白偶联受体基因GPR54的突变在人类和小鼠中导致常染色体隐性特发性低促性腺激素性性腺功能减退，提示该受体对正常促性腺激素释放激素生理学和青春期至关重要。
