Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q

The melanocortin-4, receptor (MC4R) is a seven, transmembrane G-protein-cou pled receptor whose ligand, alpha-melanocyte-stimulating hormone (alpha-MSH ), is a posttranslational derivative of pro-opiomelanocortin (POMC). The re gulatory pathway, of which MC4R is a part, has become an area of intense in terest because of its potential role in obesity. Three studies have identif ied individuals with dominantly inherited obesity segregating with mutation s in the MC4R gene. It has been hypothesized that the mutation found in the se subjects resulted in a loss of gene function resulting in obesity due to haploinsufficiency of the MC4R gene. We have been studying the molecular b asis of the phenotype of individuals with large deletions of chromosome 18q . Due to its location at 18q21.3, the MC4R gene is hemizygous in approximat ely one-third of the individuals in our study. If hemizygosity of the MC4R gene results in haploinsufficiency-induced obesity, then individuals with d eletions of 18q whose deletions include the MC4R gene should be obese in co mparison with those individuals whose deletion does not include the gene. O ur data indicate no difference in obesity among those deleted and not delet ed for the gene. This supports the hypothesis that the MC4R gene product is haplosufficient and the involvement of MC4R in obesity may reflect a domin ant negative effect.