The GPR54 Gene as a Regulator of Puberty

The first known step in sexual maturation at puberty is the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. Pubertal changes also include accelerated linear growth and adrenal maturation. The authors used complementary genetic approaches in both humans and mice to study a gene ostensibly involved in the onset of puberty. Linkage analysis and candidate-gene screening were used to identify mutations in GPR54, a gene that encodes a G protein-coupled receptor. Mutations of GPR54 were sought in members of a large, consanguineous Saudi Arabian family who lacked pubertal development. There were 3 marriages between first cousins in the family. Six of 19 offspring, 4 men and 2 women, met criteria for idiopathic hypogonadotrophic hypogonadism. Diagnosis required inappropriately low gonadotropin levels, prepubertal concentrations of sex steroids, normal anterior pituitary function, and negative brain imaging. Controls for genetic analysis included 80 North Americans, 50 Middle Eastern persons, and 50 black persons from North America. In addition, 63 patients with normosmic idiopathic hypogonadotrophic hypogonadism and 20 patients with anosmic idiopathic hypogonadotrophic hypogonadism (Kallmann's syndrome) were screened for coding-sequence mutations in GPR54. Affected persons in the study family were homozygous for an L148S mutation in GPR54. An unrelated proband with idiopathic hypogonadotrophic hypogonadism had 2 distinct mutations, R331X and X399R. The patient carrying the compound mutations had reduced secretion of endogenous GnRH and a left-shifted dose-response curve for GnRH compared with 6 hypogonadal patients who lacked GPR54 mutations. A Gpr54-deficient mouse model was phenotyped, and responsiveness to exogenous GnRH was determined. These mice had isolated hypogonadotrophic hypogonadism as evidenced by small testes in males and, in females, a delayed vaginal opening and a lack of follicular maturation. The mice were, however, responsive to both exogenous gonadotropins and GnRH, and they had normal hypothalamic levels of GnRH. These findings indicate that the receptor gene GPR54 is essential for normal secretion of GnRH and the occurrence of puberty.