Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene

Recently, haploinsufficiency mutations in the melanocortin-4 receptor gene (MC4-R) were detected which were assumed to lead to the phenotype of extrem e obesity. Previously, we detected three obese carriers among 306 index pat ients. Here we describe the detection of one haploinsufficiency carrier in an additional study group of 186 obese individuals, We subsequently genotyp ed and phenotyped 43 family members of these four index patients, two of wh om were second-degree cousins. A total of 19 carriers were identified. Extr eme obesity was the predominating phenotype. However, moderate obesity occu rred in three of the carriers. No other specific phenotypic abnormalities w ere detected. Female haploinsufficiency carriers were heavier than male car riers in the respective families, a finding similar to findings in MC4-R-kn ockout mice. In conclusion, our data fully support the etiologic role of MC 4-R haploinsufficiency mutations in obesity.