Endocrine Abstracts

The human pubertal development is a very complex biological process that can be influenced by multiple factors including the genetic ones. A growing list of genes has been implicated in the pathogenesis of the congenital isolated hypogonadotropin hypogonadism (IHH) pointing to the complexity of the genetic basis of this condition. These genes encode peptides, which are involved in the development and migration of GnRH neurons or in regulation of synthesis, secretion and action of GnRH. Among several distinct genes associated with IHH, two neuropeptides are the main regulators of the GnRH secretion: Kisspeptin and its receptor KISS1R and neurokinin B (TAC3) and its cognate receptor TACR3. Inactivating mutations have been identified in KAL1, GNRHR, FGFR1, KISS1 and KISS1R, PROK2 and PROK2R and more recently in TAC3 and TACR3 genes in patients with congenital IHH.

Central precocious puberty (CPP) has a striking predominance among girls, and in most cases is considered idiopathic. However, a familial history of early sexual maturation in girls with idiopathic CPP suggests a genetic basis for this condition. We hypothesized that gain-of-function mutations of KISS1 or of KISS1R genes might be associated with CPP. The new heterozygous mutation R386P in the GPR54 gene was identified in a Brazilian girl with CPP, the first evidence of non-constitutively dominant activating mutation of GPR54 related to the development of precocious puberty in humans. Functional study of this unique GPR54 mutation demonstrated a prolonged activation of intracellular GPR54 signaling pathways in response to kisspeptin. We also investigated the presence of potential variants in KISS1 gene and the new heterozygous P74S mutation was found in a boy with CPP. The capacity to stimulate signal transduction was significantly greater for P74S compared to the wild type after pre incubation of wild type and mutant kisspeptins with human serum, indicating that the mutant was more resistance to degradation.

Most of the identification of the molecular defects came from well characterized human phenotypes. The several emerging next-generation sequencing technologies for whole genome analyses surely will allow the identification of new genes responsible for congenital pubertal disorders.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.