GPR54 and KiSS-1: role in the regulation of puberty and reproduction.

The finding of inactivating mutations in GPR54 in IHH patients and the lack of reproductive maturation of the GPR54 null mouse have uncovered a previously unrecognized role for GPR54 and KiSS-1 in the physiologic regulation of puberty and reproduction. This newly identified function for GPR54 and its cognate ligand, kisspeptin, has led to additional studies that have localized GPR54 and KiSS-1 mRNA in the hypothalamus, colocalized GPR54 in GnRH neurons, demonstrated GnRH-dependent activation of LH and FSH release by kisspeptin, and shown increased hypothalamic KiSS-1 and GPR54 mRNA levels at the time of puberty. Taken together, these findings establish the role of the kisspeptin-GPR54 system in the stimulation of GnRH neurons during puberty. The mechanisms by which kisspeptin activates GnRH release, as well as the trigger for this pathway at the onset of puberty, are yet to be elucidated. In the future, modulators of GPR54 activity, including kisspeptin, may prove valuable in clinical applications in the fields of both cancer therapy and reproductive medicine.

KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty.

The recent identification of loss-of-function mutations in the gene encoding GPR54, the receptor for the KiSS-1-derived peptides, kisspeptins, has highlighted a previously unrecognized pathway in the physiologic regulation of puberty and reproduction. Patients with loss-of-function mutations in GPR54 have idiopathic hypogonadotropic hypogonadism, and mice lacking GPR54 similarly fail to undergo puberty and have immature reproductive organs and low levels of sex steroids and gonadotropins. These observations have led to the hypothesis that kisspeptins activate hypothalamic GnRH release, thereby serving as a pivotal factor in the pubertal activation of the reproductive cascade. This hypothesis is supported by subsequent studies in rodent and primate models that have demonstrated localization of KiSS-1 mRNA in the hypothalamus, colocalization of GPR54 in GnRH neurons, GnRH-dependent activation of LH and FSH release by intracerebroventricular or peripheral administration of kisspeptin, and increased hypothalamic KiSS-1 and GPR54 mRNA levels at the onset of puberty. Taken together, these findings weave a compelling case for a role of the kisspeptin-GPR54 system in the activation of GnRH neurons at the time of pubertal awakening of the reproductive axis.

The GPR54 gene as a regulator of puberty.

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.