A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

Eur J Hum Genet. 2012 Dec;20(12):1290-4. doi: 10.1038/ejhg.2012.103. Epub 2012 May 30.


Rare mutations in several genes have a critical role in the control of homeostatic mechanisms such as food-intake, energy balance and glucose metabolism. In this study, we performed a mutational screening in a 58-year-old woman presenting early-onset type 2 diabetes and central obesity. The entire coding regions of MC4R, MC3R, HNF1A, GCK and POMC (pro-opiomelanocortin) genes were analyzed by direct sequencing. A new missense mutation was identified within the POMC gene signal peptide sequence, resulting in a heterozygous substitution of an arginine for a glycine at codon 15 (p.A15G) that was excluded in 300 healthy normal weight controls. The mutation segregated in the family and was associated with overweight, type 2 diabetes, hypertension and coronary heart disease in the carriers. Functional studies demonstrated that POMC protein was not detectable in β-TC3 cells transfected with A15G-POMC vector as well as in their culture media, despite POMC mRNA levels were comparable for amount and stability to those of wild-type-transfected cells. In silico RNA folding prediction indicated that the mutation gives rise to a different RNA secondary structure, suggesting that it might affect translation and protein synthesis. To the best of our knowledge, this is the first report addressing the functional consequences of a mutation in the signal peptide of POMC. These findings further support the hypothesis that POMC-derived peptides might have a role in the control of peripheral glucose metabolism and suggest that disruption of central POMC secretion might represent an additional link between type 2 diabetes and obesity.

Publication types

  • Case Reports

MeSH terms

  • Animals
  • Arginine / genetics
  • Cell Line, Tumor
  • Coronary Disease / diagnosis
  • Coronary Disease / genetics
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Loci / genetics
  • Glycine / genetics
  • Heterozygote
  • Humans
  • Hypertension / diagnosis
  • Hypertension / genetics
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Middle Aged
  • Mutation, Missense*
  • Obesity / diagnosis
  • Obesity / genetics*
  • Pedigree
  • Pro-Opiomelanocortin / chemistry
  • Pro-Opiomelanocortin / genetics*
  • Pro-Opiomelanocortin / metabolism
  • Protein Sorting Signals / genetics*
  • RNA Folding
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / chemistry


  • Protein Sorting Signals
  • RNA, Messenger
  • Pro-Opiomelanocortin
  • Arginine
  • Glycine