Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity

We initially performed a mutation screen of the coding region of
the MC4R in 808 extremely obese children and adolescents and 327
underweight or normal-weight controls allowing for a case-control
study. A total of 16 different missense, nonsense, and frameshift
mutations were found in the obese study group; five of these have
not been observed previously. In vitro assays revealed that nine
[the haplotype (Y35X; D37V) was counted as one mutation] of the 16
mutations led to impaired cAMP responses, compared with wild-type
receptor constructs. In contrast, only one novel missense mutation
was detected in the controls, which did not alter receptor
function. The association test based on functionally relevant
mutations was positive (P = 0.006, Fisher's exact test, one-sided).
We proceeded by screening a total of 1040 parents of 520 of the
aforementioned obese young index patients to perform transmission
disequilibrium tests. The 11 parental carriers of functionally
relevant mutations transmitted the mutation in 81.8% (P = 0.033;
exact one-sided McNemar test). These results support the hypothesis
that these MC4R mutations represent major gene effects for obesity.