A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans.

As a mediator of the effects of leptin, the melanocortin-4 receptor (MC4R) is an essential component of the central regulation of long-term energy homeostasis. Heterozygous mutations in this receptor are the most frequent genetic cause of severe obesity in children. The very rare described carriers of homozygous MC4R mutations for whom clinical data were available had a residual receptor activity thus not allowing for the description of the full extent of the role of MC4R in humans. Here, we present the clinical and biological features of a patient with complete absence of MC4R activity and compare the clinical and endocrine characteristics of this patient with those previously observed in leptin receptor-deficient patients. Our data suggest that in humans, the MC4R mediates most of the anorectic effects of leptin in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations.