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

Katie Duckett1, Alice Williamson1, John W R Kincaid1

  • 1Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

The Journal of Clinical Endocrinology and Metabolism
|June 20, 2023
PubMed
Abstract

Insights

Deleterious variants in the melanocortin 3 receptor (MC3R) gene are more common in individuals with constitutional delay of growth and puberty (CDGP). However, MC3R variants are not a frequent cause of CDGP.

Area of Science:

  • Endocrinology
  • Genetics
  • Human Physiology

Background:

  • The melanocortin 3 receptor (MC3R) is a key regulator of pubertal timing, linear growth, and lean mass.
  • Population studies indicate MC3R variants are linked to later puberty onset.
  • The prevalence of MC3R variants in patients with pubertal disorders is unknown.

Purpose of the Study:

  • To investigate if deleterious MC3R variants are more frequent in patients with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

Main Methods:

  • Sequencing of MC3R in 362 CDGP patients and 657 nIHH patients.
  • Experimental characterization of MC3R variant signaling properties.
  • Comparison of variant frequencies against a large population-based control cohort and UK Biobank participants.

Main Results:

  • MC3R loss-of-function variants were overrepresented in CDGP patients (2.2%) compared to controls.
  • No significant overrepresentation of MC3R variants was found in nIHH patients (0.6%).
  • Predicted deleterious MC3R variants were more frequent in women with self-reported delayed menarche (≥16 years) in the UK Biobank.

Conclusions:

  • Functionally damaging MC3R variants are overrepresented in individuals with CDGP.
  • MC3R variants are not a common cause of CDGP, despite their association.
Keywords:
MC3RALSPACUK Biobankconstitutional delaydelayed puberty

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