Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty

Abstract

Context: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.

Objective: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

Methods: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort.

Results: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07).

Conclusion: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Keywords: MC3R; ALSPAC; UK Biobank; constitutional delay; delayed puberty.

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, V_max (%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.