The melanocortin-4 receptor (MC4R) is a seven, transmembrane G-protein-coupled receptor whose ligand, alpha-melanocyte-stimulating hormone (alpha-MSH), is a post-translational derivative of pro-opiomelanocortin (POMC). The regulatory pathway, of which MC4R is a part, has become an area of intense interest because of its potential role in obesity. Three studies have identified individuals with dominantly inherited obesity segregating with mutations in the MC4R gene. It has been hypothesized that the mutation found in these subjects resulted in a loss of gene function resulting in obesity due to haploinsufficiency of the MC4R gene. We have been studying the molecular basis of the phenotype of individuals with large deletions of chromosome 18q. Due to its location at 18q21.3, the MC4R gene is hemizygous in approximately one-third of the individuals in our study. If hemizygosity of the MC4R gene results in haploinsufficiency-induced obesity, then individuals with deletions of 18q whose deletions include the MC4R gene should be obese in comparison with those individuals whose deletion does not include the gene. Our data indicate no difference in obesity among those deleted and not deleted for the gene. This supports the hypothesis that the MC4R gene product is haplosufficient and the involvement of MC4R in obesity may reflect a dominant negative effect.