Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
复制标题
DOI：
10.1073/pnas.1834399100
复制
发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Milgrom, E
中科院分区：
文献类型：
--
作者：
de Roux, N;Genin, E;Milgrom, E
促性腺激素减退症是指垂体腺分泌卵泡刺激素和黄体生成素不足，导致青春期成熟和生殖功能受损。在没有垂体或下丘脑解剖损害和嗅觉障碍(Kallmann综合征)的情况下，低促性腺激素减退被称为孤立性低促性腺激素减退(IHH)。少数IHH病例是由于促性腺激素释放激素受体功能丧失突变所致。为了确定导致IHH的其他基因缺陷，研究了一个有五个受影响兄弟姐妹且具有正常促性腺激素释放激素受体编码序列的大型血缘家庭。纯合子全基因组图谱可以在19号染色体(19p13)的短臂内定位一个新的基因座。对位于该区域内的几个基因进行测序表明，该家族中所有受影响的兄弟姐妹都携带着Gpr54基因155个核苷酸的纯合缺失。该缺失包括内含子4-外显子5连接的剪接受体位点和外显子5的一部分。在未患病的家系成员中，只有一个等位基因缺失或存在缺失。GPR54已被初步鉴定为孤儿G蛋白偶联受体，与甘丙肽受体有40%的同源性。最近，来源于Kiss1蛋白的54-aa多肽被鉴定为Gpr54的配体。目前的研究表明，GPR54功能丧失是IHH的原因之一，它确认GPR54和可能的Kiss1蛋白衍生肽在促性腺激素轴的生理学中发挥着以前未被怀疑的重要作用。
Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. in the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.