Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency

Over 20 severely obese subjects in 11 independent kindreds have been report ed to have pathogenic heterozygous mutations in the gene encoding the melan ocortin 4 receptor (MC4R), making this the most common known monogenic caus e of human obesity. To date, the detailed clinical phenotype of this domina ntly inherited disorder has not been defined, and no homozygous subjects ha ve been described. We determined the nucleotide sequence of the entire codi ng region of the MC4R gene in 243 subjects with severe, early-onset obesity . A novel two-base pair GT insertion in codon 279 was found in two unrelate d subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, a nd one mutation (T112M) reported previously were found in five subjects. N6 2S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Sev eral features of the phenotype, e.g. hyperphagia, tendency toward tall stat ure, hyperinsulinemia, and preserved reproductive function, closely resembl e those reported previously in Mc4r knock-out mice. In addition, a marked i ncrease in bone mineral density was seen in all affected subjects. In trans ient transfection assays, the N62S mutant receptor showed a responsiveness to alpha MSH that was intermediate between the wild-type receptor and mutan t receptors carrying nonsense and missense mutations associated with domina ntly inherited obesity. Thus MC4R mutations result in a syndrome of hyperph agic obesity in humans that can present with either dominant or recessive p atterns of inheritance.