Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pat Show more
Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants. Our results significantly correlated with previously published pathogenic categories (r = 0.623; The functional data provided here can assist in the reclassification of several VUS in Show less
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cell Show more
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed. Show less