The GPR54 gene as a regulator of puberty.
The GPR54 gene as a regulator of puberty.
复制标题
DOI：
10.1097/00006254-200405000-00020
复制
发表时间：
2004-05
期刊：
影响因子：
--
通讯作者：
S. Seminara;S. Messager;E. Chatzidaki;R. Thresher;J. Acierno;Jenna K Shagoury;Y. Bo-Abbas;W. Kuohung-W.-Ku
中科院分区：
文献类型：
--
作者：
S. Seminara;S. Messager;E. Chatzidaki;R. Thresher;J. Acierno;Jenna K Shagoury;Y. Bo-Abbas;W. Kuohung-W.-Ku
青春期是一个复杂的生物学过程，涉及性发育、加速线性生长和肾上腺成熟，当下丘脑开始分泌促性腺激素释放激素时就开始了。我们在人类和老鼠身上进行了研究，以确定决定青春期开始的遗传因素。方法在人和小鼠中采用互补遗传方法。一个近亲家庭成员缺乏青春期发育（特发性促性腺功能低下）被检查突变的候选基因，GPR54，编码一个G蛋白偶联受体。在体外检测野生型和突变型GPR54的功能差异。同时，建立gpr54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。结果指数家系中受影响的患者GPR54 L148S突变为纯合子，而与特发性促性腺功能减退症无关的先证者被确定具有两个单独的突变，R331X和X399R。体外转染具有突变结构的COS-7细胞显示肌醇磷酸的积累显著减少。携带复合杂合突变（R331X和X399R）的患者与6例未携带GPR54突变的特发性促性腺功能低下患者相比，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缺陷小鼠有单独的促性腺功能减退（雄性小鼠睾丸小，雌性小鼠阴道开口延迟，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，下丘脑促性腺激素释放激素水平正常。结论：G蛋白偶联受体基因GPR54的突变可导致人类和小鼠常染色体隐性特发性促性腺功能低下，表明该受体对正常的促性腺激素释放激素生理和青春期至关重要。
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.