In the liver, PAH metabolizes L-Phe to tyrosine (L-Tyr) and its deficiency in humans leads to HPA and severe mental retardation unless adequate treatment is implemented.20 Several orthologous mouse models of HPA and PKU have been generated by germline mutagenesis, followed by molecular characterization.21 The here presented Pahenu2 mouse model carries a p.Phe263Ser missense mutation in the Pah gene. Here, PAH is linked to phenylketonuria.