LEP and obesity due to melanocortin 4 receptor deficiency: Although causative mutations are difficult to confirm, mutations in most genes of the leptin-melanocortin pathway that cause hyperphagia and severe obesity in humans and mice are, in particular, pathogenic mutations in the MC4R gene, which have been found in up to 5% of cases of early childhood obesity and up to 0.3% of the general population (7, 13).