Human diseases associated with GPR54 mutations

G protein-coupled receptor 54 (GPR54) was first described as an orphan receptor in the rat brain one decade ago. At that time, all we knew about this receptor was that it had a high homology with other G protein-coupled receptors, like galanin receptors. Later, its endogenous ligand, kisspeptin, was identified and the kisspeptin-GPR54 system became one of the most important excitatory neuroendocrine regulators of puberty initiation. Several loss-of-function mutations in GPR54 gene were described to be associated with sporadic and familial normosmic isolated hypogonadotropic hypogonadism phenotype in humans. Consistent with this fact, knockout mice for gpr54(-/-) recapitulated the human phenotype of the lack of reproductive maturation. On the other hand, a unique activating mutation (R386P) was recently described in this receptor in a girl with central precocious puberty. This missense mutation located at carboxy-terminal tail of the GPR54 leads to prolonged activation of intracellular signaling pathways in response to kisspeptin, suggesting an uncommon model of G protein-coupled receptor activation. This chapter will describe the kisspeptin-GPR54 complex physiology and its current role in human diseases.