Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

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 nonobese control subjects 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 noncarriers from three generations.RESULTS-Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P ϭ 6.9 ϫ 10 Ϫ10 ). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier 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 Ͼ52 years, 60% in 18-to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at Ͼ40 years).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 preventing the development of obesity even in those strongly genetically predisposed to it.

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

“…One sister studied for the MC4R gene has the obese phenotype but does not carry the p.H76R mutation. This result is in concordance with the literature stating that this MC4R missense mutation is not associated with the morbid obesity phenotype (Stutzmann et al, 2008).…”

“…Other authors defended an age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, related to the development of an "obesogenic" environment. It may contribute to the coexistence of obese noncarrier individuals among relatives of those strongly genetically predisposed (Stutzmann et al, 2008).…”

“…It is thought to explain 2-6% of extremely obese childhood and adolescent cases (Farooqi et al, 2003;Hinney et al, 2003Hinney et al, , 2006Santini et al, 2004;Wang & Tao, 2011). The MC4R is a membrane-bound G-protein-coupled receptor that activates adenylate cyclase; in response to the α-melanocyte-stimulating hormone (α-MSH), MC4R induces production of cAMP (Stutzmann et al, 2008;Caruso et al, 2013). The expression of MC4R is restricted to the brain, where it is found in hypothalamic nuclei involved in food intake regulation (Mountjoy et al, 1994).…”

Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant

“…This locus is monomorphic for the valine allele in the 426 Pima Indians in whom the gene was sequenced. A recent meta-analysis in a large group of Europeans found that a range of functional MC4R variants were more common in obese than lean individuals (28). In a German population study, R165Q was rare (minor allele frequency 1.2 ϫ 10 Ϫ4 ) and the individual was not obese (26).…”

20 YEARS OF LEPTIN: Human disorders of leptin action

“…As MC4R deficiency is the most common genetic form of obesity, assessment of the sequence of the MC4R is increasingly seen as a necessary part of the clinical evaluation of the severely obese child. Other genetic and environmental modifiers can affect the degree of obesity associated with MC4R mutations in some pedigrees (Stutzmann et al 2008), as such co-dominance, with modulation of expressivity and penetrance of the phenotype, seems an appropriate descriptor for the mode of inheritance (Farooqi et al 2003).…”