Homozygous MC4R mutations, M161T and I316S, identified separately in 2 subjects (3.2%), were associated with severe obesity, hyperphagia, hyperleptinemia and hyperinsulinemia.
A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding.
Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.
As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04).
MC4R are necessary for melanocortin agonist-induced weight loss and improvements in liver metabolism, but are not required for improvements in hyperinsulinemia.
MC4R variants were detected in three patients: the known I169S variant was found in heterozygote state in two patients and a novel heterozygous Y302F mutation was detected in one 12-year-old girl (BMI = 34 kg/m(2), BMI z-score 2.7) who has been overweight since the second year of life and suffered from hyperinsulinemia (at the age of 12: fasting insulin 45 mU/ml, after oral glucose load max.300 mU/ml).