Tryptophan hydroxylase 2 (TPH2) is the key and rate-limited enzyme of serotonin (5-HT) synthesis in the brain. TheC1473Gmutation in theTph2gene results in a two-fold decrease in enzyme activity in the mouse brain. Thelethal yellow(AY) mutation in theRaly-Agoutilocus results in the overexpression of theAgoutigene in the brain and causes obesity and depressive-like behavior in mice. Herein, the possible influences of these mutations and their combination on body mass, behavior, brain 5-HT and melanocortin systems in mice of the B6-1473CC/aa. B6-1473CC/AYa, B6-1473GG/aa are investigated. B6-1473GG/AYagenotypes were studied. The1473GandAYalleles increase the activity of TPH2 and the expression of theAgoutigene, respectively, but they do not alter 5-HT and 5-HIAA levels or the expression of the genesTph2,Maoa,Slc6a4,Htr1a,Htr2a,Mc3randMc4rin the brain. The1473Gallele attenuates weight gain and depressive-like immobility in the forced swim test, while theAYallele increases body weight gain and depressive-like immobility. The combination of these alleles results in hind limb dystonia in the B6-1473GG/AYamice. This is the first evidence for the interaction between theC1473GandAYmutations.