Heterozygosity for a POMC-null mutation and increased obesity risk in humans.

Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. The concept that subtle variation in POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage of obesity-related traits to a locus on chromosome 2p22 encompassing the POMC gene. We identified a novel homozygous frameshift (C6906del) mutation in POMC in a child of Turkish origin with severe obesity and hypoadrenalism. This mutation would be predicted to lead to the loss of all POMC-derived peptides. The availability of a large extended pedigree provided the opportunity to address whether loss of one copy of the POMC gene was sufficient to alter obesity risk. Twelve relatives were heterozygous for the mutation and 7 were wild type. Of the heterozygotes, 11 of 12 heterozygotes were obese or overweight compared with only 1 of 7 of the wild-type relatives. The mean BMI SD score was 1.7 +/- 0.5 in heterozygotes and 0.4 +/- 0.4 in the wild-type relatives. Parametric linkage analysis of the trait "overweight" provided statistically significant evidence of linkage with this locus, with a maximum "location score" (comparable with multipoint logarithm of odds scores) of 3.191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity.