Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index.

T he melanocortin-4 receptor gene (MC4R) is involved in central energy homeostasis and body weight regulation. Both endogenous anorexigenic and orexigenic ligands bind to the receptor. Under normal conditions, the anorexigenic tone prevails as revealed by the fact that Mc4r knockout mice develop elevated body weight. Mc4r mice show higher food intake but a similar metabolic rate and similar decreased physical activity compared to wild type (WT) mice of the same strain. In comparison to a standard low fat diet, this deviant regulation of energy homeostasis is even more pronounced upon intake of a moderately fat diet, which leads to an even higher body mass. In all studies, the effect on body weight is smaller in heterozygous than in homozygous knockout mice, but the exact degree of dominance is not clear. In heterozygous Mc4r animals, body mass is increased on average by about 7–45% and in homozygous Mc4r by 50–100% compared to WT with substantial overlap between groups. The mutations might have a sex dependent effect, but the results are contradictory. In one study, the effect in males was only about half of that in females. However, two studies did not detect a sex by genotype interaction in this Mc4r strain. 5 One study in a different knockout line of the same inbred strain found a sex by genotype interaction in the opposite direction, with only a marginal effect in heterozygous females whereas heterozygous males had a body weight intermediate between WT and homozygous knockouts. The first mutations in the human MC4R gene were reported in extremely obese probands. Since then, several other studies investigated the association of different MC4R mutations with obesity. According to a recent overview, at least 34 putatively functionally relevant variants have been detected in several mutation screens. The variants encompass frameshift, nonsense, and missense mutations, most of which have been shown to lead to total or partial loss of function in appropriate in vitro assays. All mutations are rare, with reported combined frequencies for all functionally relevant mutations typically in the range of 2–3% in extremely obese individuals. In contrast, none of the putatively functionally relevant mutations have been found in controls. The two missense variants V103I and I251L have each been detected with similar frequencies in both cases and controls; I251L is presumed to be a non-functional polymorphism, while V103I shows a negative association with obesity as has recently been shown in a meta-analysis encompassing more than 7500 individuals. The quantitative effect of human MC4R mutations on body weight is currently unknown. Often the study design of screening phenotypically selected probands, for example extremely obese cases and normal weight controls, precludes such an analysis. It is assumed that these mutations more or less completely underlie the obesity of the respective carrier and this therefore is often referred to as a monogenic form of obesity. However, in family studies based on obese index carriers, single relatives harbouring the same mutation have been identified who were only moderately overweight or even lean. 17 Whereas this can be explained by an underlying medical condition in single cases, the lean carriers identified by Vaisse et al were healthy. Recently, three missense mutations (which have not yet been functionally characterised) have also been found in a group of 48 controls with a body mass index (BMI) below 30 kg/m. Assessment of the effect size of MC4R mutations is further complicated by the fact that WT relatives of extremely obese mutation carriers are often also obese, 17 19 20 indicating that other genetic and/ or environmental factors are operative in these families, which accordingly could also contribute to the obesity of the index cases. It is well known that body weight is influenced by many genetic and environmental factors. Heritability estimates for BMI derived from family and twin studies range