Abstract

Objective. Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However there is uncertainty regarding the degree of penetrance of this condition and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.

Research Design and Methods. We determined the MC4R sequence in 2,257 obese individuals and 2,677 non-obese controls of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees including 97 carriers and 94 non-carriers from 3 generations.

Results. 68% of the MC4R non synonymous mutations found in obese subjects result in a loss of function in vitro. They were found in 1.72% of obese vs. 0.15% of non-obese people (p=6.9x10^-10). Among the families, abnormal eating behaviour was more frequent in both MC4R-deficient children and adults than in non-carriers. While BMI was inversely associated with educational status in non-carrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged>52 years, 60% in 18-52 year-old adults and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20yrs vs. 60% at >40yrs).

Conclusions. We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to prevent the development of obesity even in those strongly genetically predisposed to it.