G protein-coupled receptors involved in GnRH regulation: Molecular insights from human disease

Abstract

In the past two decades, an increasing body of evidence has demonstrated that several G protein-coupled receptor (GPCR)-ligand pairs are critical for normal human reproductive development and function. Patients harboring genetic insults in either the receptors or their cognate ligands have presented with reproductive disorders characterized by varying degrees of GnRH deficiency. These disorders include idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann Syndrome (KS). Conversely, mutations in some of these ligand-receptor pairs have been associated with accelerated reproductive maturation, manifested as central precocious puberty (CPP). To date, a series of elegant studies have characterized four GPCRs that play important roles in the neuroendocrine control of human reproductive development and function: GnRHR, KISS1R, PROKR2 and NK3R. Furthermore, these studies provide insights into the mechanisms by which mutations in these receptors give rise to reproductive disease phenotypes. This report will review mutations identified in GPCRs involved in the neuroendocrine control of the human reproductive axis with the aims of elucidating structure-function relationships of these GPCRs and identifying correlations between these structure-function relationships and the genotypic-phenotypic characterization of the patients.

Reliability of pubertal maturation self-assessment in a school-based survey

“…It is more crucial in certain conditions regarding abnormal pubertal development such as precocious or delayed puberty (1,2). Accurate assessment of pubertal maturation can help in counseling adolescents and their parents regarding the appropriate age of onset and progression of secondary sex characteristics, the timing of the pubertal growth spurt, the age at menarche, and sometimes the age of the adolescent reaching his/her final height.…”

Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction

“…Bioinformatics approaches have been used to predict intrinsically disordered regions of GPCRs - regions lacking a stable three-dimensional structure and playing a role in intra- and extracellular plasticity and protein-protein interactions of GPCRs - and regions predicting G protein coupling specificity [11, 12]. In the GPCR family, gonadotropin-releasing hormone receptor (GnRHR), kisspeptin receptor (KISS1R), prokineticin receptor 2 (PROKR2), and tachykinin receptor 3 (TACR3) have been found to play key roles in the central neuroendocrine regulation of reproductive function [13]. In these GPCRs, more than 300 missense variants have been found, either from patients with phenotypic reproductive disorders or from large-scale genomic sequencing of general populations.…”

“…In these GPCRs, more than 300 missense variants have been found, either from patients with phenotypic reproductive disorders or from large-scale genomic sequencing of general populations. Some of the variants identified in patients with reproductive disorders have undergone in vitro biological function testing [13, 14], which has aided in the interpretation of the pathogenic relationship between genotype and phenotype. Computational prediction results from S orting I ntolerant F rom T olerant (SIFT) and Poly morphism Phen otyping-2 (PolyPhen-2) are available for most of the variants, but the correlation between in silico prediction and in vitro biological function for these GPCR missense variants has not been well established.…”

Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice

“…Furthermore, they sense hormones secreted by the gonads. Gonadal hormones are capable of acting on GnRH neurons directly via nongenomic [26,27] and longer-lasting, genomic mechanisms [28], the latter mediated by gonadal steroid receptors for female and male sex hormones [11,29,30,31,32,33]. In addition to influencing GnRH neurons directly, gonadal hormones exert feedback action on steroid receptor-expressing interneuron populations that are wired to GnRH neurons via communicating synapses [34,35,36].…”