Endocrine Abstracts

The mechanisms controlling the timing of puberty remain largely unknown. Recent insights into genetic causes of pubertal disorders have provided important advances in our understanding of the physiology underlying this developmental process. Mutations in genes important in neuroendocrine pathways controlling GnRH release and LH and FSH secretion have been identified in patients with isolated hypogonadotropic hypogonadism, Kallmann syndrome, and central precocious puberty. Many of the genes implicated encode G protein-coupled receptors (GPCRs) and their cognate ligands, including: i) KISS1/KISS1R, encoding kisspeptin and its receptor (KISS1R), ii) TAC3/TACR3, encoding neurokinin B and the neurokinin 3 receptor (NK3R), iii) PROK2/PROKR2, encoding prokineticin 2 and prokineticin receptor 2 (PROKR2), and iv) GNRH1/GNRHR, encoding GnRH itself and its receptor, GnRHR. Mutations in these GPCRs have been described in both heterozygous and homozygous states in patients with varying degrees of GnRH dysregulation. These mutations have been identified in diverse functional domains of the receptors. Elucidation of structure-function relationships for these GPCRs and of the key mechanisms by which their activation mediates cellular and biological responses have become increasingly important for our understanding of the reproductive abnormalities resulting from mutations in these genes. The identification of the critical domains of these receptors important for their activity and of their downstream pathways of signaling will advance our understanding of the function of these receptors in the control of GnRH release.

Declaration of funding

This work was supported by NIH (grant numbers U54 HD28138, R01 HD19938, R01 HD61577, and R21 HD66495).