Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity

J Clin Endocrinol Metab. 2005 Jan;90(1):219-24. doi: 10.1210/jc.2004-0497. Epub 2004 Oct 14.


Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 +/- 2.4 kg/m(2)) and 706 control subjects (body mass index 21.4 +/- 2.1 kg/m(2)) for mutations in MC4R. A total of 14 different mutations were identified of which two, Ala219Val and Leu325Phe, were novel variants. The variant receptor, Leu325Phe, was unable to bind [Nle4,d-Phe7]-alphaMSH, whereas the Ala219Val variant showed a significantly impaired melanotan II induction of cAMP, compared with the wild-type receptor. The remaining 11 mutations have previously been reported, but selected MC4R variants were further characterized in vitro in the present study. A previously identified nonsense mutation, Tyr35stop, had a relatively high allele frequency (0.6%), suggesting a possible founder effect in the Danish population. This study shows a carrier frequency of 2.5% of pathogenic mutations in the MC4R gene in a population-based study of obese men. Thus, variation in this gene is the most common known specific genetic cause of obesity among Scandinavian men.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cohort Studies
  • Humans
  • Male
  • Mutation*
  • Obesity / genetics*
  • Receptor, Melanocortin, Type 4 / genetics*
  • Receptor, Melanocortin, Type 4 / physiology


  • Receptor, Melanocortin, Type 4