de Roux Nicolas
Laboratoire d'Hormonologie et Biologie Moléculaire, Hôpital de Bicêtre, Le Kremlin-Bicêtre, and INSERM U584, Faculté de Médecine Necker-Enfants Malades, Paris, France.
Horm Res. 2005;64 Suppl 2:48-55. doi: 10.1159/000087754.
Hypogonadotropic hypogonadism has been described in several human genetic diseases. Congenital isolated hypogonadotropic hypogonadism is classified into two categories: one that is associated with anosmia (Kallmann syndrome) and one that is apparently isolated. Mutations and deletions of the KAL1 gene, which encodes for a protein involved in cell adhesion, have been observed in many cases of the X-linked form of Kallmann syndrome. Recently, loss-of-function mutations of fibroblast growth factor receptor-1 (FGFR1) were associated with an autosomal dominant form of Kallmann syndrome. Genotype-phenotype correlations confirm the large spectrum of the phenotype due to FGFR1 mutations. Cases of isolated hypogonadotropic hypogonadism were considered to be idiopathic until the description of mutations of the gonadotropin releasing hormone receptor, luteinizing hormone and follicle stimulating hormone genes. However, defects in these genes only account for a small percentage of familial cases, which suggests that other proteins may be involved in regulation of the gonadotropic axis. We recently described GPR54 as one of these proteins by genome mapping in a very informative family. In vivo studies and genotype-phenotype correlations indicate that gonadotropic axis regulation by GPR54 occurs mainly at the level of the hypothalamus.
促性腺激素缺乏性性腺功能减退已在多种人类遗传疾病中有所描述。先天性孤立性促性腺激素缺乏性性腺功能减退分为两类：一类与嗅觉缺失有关（卡尔曼综合征），另一类明显是孤立性的。在许多X连锁型卡尔曼综合征病例中，已观察到编码参与细胞黏附蛋白的KAL1基因发生突变和缺失。最近，成纤维细胞生长因子受体1（FGFR1）的功能丧失突变与常染色体显性遗传型卡尔曼综合征相关。基因型与表型的相关性证实了由于FGFR1突变导致的表型范围广泛。在促性腺激素释放激素受体、促黄体生成素和促卵泡生成素基因的突变被描述之前，孤立性促性腺激素缺乏性性腺功能减退病例被认为是特发性的。然而，这些基因的缺陷仅占家族性病例的一小部分，这表明其他蛋白质可能参与促性腺轴的调节。我们最近通过对一个信息丰富的家族进行基因组定位，将GPR54描述为这些蛋白质之一。体内研究和基因型与表型的相关性表明，GPR54对促性腺轴的调节主要发生在下丘脑水平。
