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.
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.
Laboratory of Molecular Biology, Istituto Auxologico Italiano, Milano, Italy.
Monica
M
Mencarelli
Alessandra
A
Zulian
Raffaella
R
Cancello
Luisella
L
Alberti
Luisa
L
Gilardini
Anna Maria
AM
Di Blasio
Cecilia
C
Invitti
D000818:Animals; D001120:Arginine / Q000235:genetics; D045744:Cell Line, Tumor; D003327:Coronary Disease / Q000175:diagnosis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D009765:Obesity / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D011333:Pro-Opiomelanocortin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D021382:Protein Sorting Signals / Q000235:genetics*; D059370:RNA Folding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000737:chemistry
D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D001120:Arginine; D005998:Glycine