Endocrine Abstracts

The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic–pituitary–gonadal axis. In the last 5 years, several loss-of-function mutations in the G-protein coupled receptor 54 (GPR54) gene have been shown to cause isolated hypogonadotropic hypogonadism. Although these mutations are not a common cause of hypogonadotropic hypogonadism, patients bearing mutations are critical to explore genotype-phenotype and gene function. The ligands for GPR54 are derived from the precursor protein, kisspeptin. The kisspeptins have been characterized as fundamental regulators of pubertal onset and powerful stimulants for GnRH-induced gonadotropin secretion. More recently, a GPR54 missense mutation (R386P) was reported in a girl with idiopathic gonadotropin-dependent precocious puberty. Functional studies in vitro demonstrated that this mutation leads to sustained activation of intracellular signaling pathways downstream of GPR54, suggesting that GPR54 defects can be also associated with central precocious puberty phenotype.