Figure 1.
Functional characterization of melanocortin 3 receptor (MC3R) coding mutations in constitutional delay of growth and puberty (CDGP) and population cohorts. A, Schematic showing locations of identified nonsynonymous variants in Manchester UK CDGP, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), Delayed Puberty Genetic Consortium (DPGen), and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. F45S has already been characterized as complete loss-of-function (CLoF), and R220S as partial loss-of-function (PLoF). B to D, cyclic adenosine monophosphate (cAMP) dose-response curves on treatment with NDP-MSH classified as CLoF, PLoF, and wild-type (WT)-like variants, respectively. Error bars = SEM, N reported in Supplementary Materials. E and F, Vmax (%WT) and logEC50 values plotted for all variants except I50T (Supplementary Materials) calculated from dose-response curves. Dotted line indicates WT response. Individual crosses represent biological replicates. Asterisk represents Bonferroni P less than .05 via 2-way analysis of variance compared to WT. ND, not determined.