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.
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