A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

Hum Mol Genet. 2002 Aug 15;11(17):1997-2004. doi: 10.1093/hmg/11.17.1997.


The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between beta melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case-control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Insufficiency / genetics
  • Animals
  • CHO Cells
  • Case-Control Studies
  • Cricetinae
  • DNA Mutational Analysis
  • DNA Primers / chemistry
  • Disease Susceptibility
  • Female
  • Hair Color / genetics
  • Humans
  • Male
  • Mutation, Missense / genetics*
  • Obesity / etiology
  • Obesity / genetics*
  • Pedigree
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / metabolism
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Precipitin Tests
  • Pro-Opiomelanocortin / genetics*
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin / metabolism
  • Recombinant Fusion Proteins / metabolism
  • beta-Endorphin / metabolism
  • beta-MSH / metabolism


  • DNA Primers
  • Peptide Fragments
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin
  • Recombinant Fusion Proteins
  • beta-MSH
  • beta-Endorphin
  • Pro-Opiomelanocortin