A novel human monogenic obesity trait: severe early-onset childhood obesity caused by aberrant expression of agouti-signaling protein (ASIP): a case report

Abstract

In a patient with extreme childhood obesity, we identified a heterozygous tandem duplication at the ASIP (agouti-signaling protein) gene locus causing ubiquitous, ectopic ASIP expression. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase (ITCH) promoter, driving the ubiquitous generation of ASIP as evidenced in patient-derived induced pluripotent stemm cells for all germ layers. The patient´s phenotype of early-onset obesity, overgrowth, red hair, and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog agouti. ASIP represses melanocyte-stimulating hormone-mediated activation of as an inverse agonist of the melanocortin receptors, thereby affecting eating behavior, energy expenditure, adipocyte differentiation, and pigmentation, as observed in the index patient. Furthermore, we identified another patient with the identical mutation, ectopic ASIP expression and a similar phenotype. Thus, human obesity caused by ubiquitous ASIP expression is a novel monogenic trait, potentially treatable by melanocortin receptor agonists.