ABSTRACT
Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH), and is performed with newborn mass screening. PKU causes irreversible mental retardation that can be prevented by a strict low-phenylalanine diet. More than 100 different mutations have been identified world wide and it has been revealed that PKU is a highly heterogeneous disorder. Here, we describe the progress of the molecular genetics of PKU in East Asia. Approximately 60% of all PKU alleles in East Asians have been characterized with 10 PKU mutations. Two major PKU mutations, R413P and IVS4nt-1, may have originated in different populations, spreading in prehistoric times through the Asian continent due to the founder effect, genetic drift, and bottleneck effect. We found different mutations in Caucasians and East Asians, thus PKU mutations have occurred after ethnic divergence between Caucasians and East Asians. Furthermore, PKU genotype and in vitro PAH activity in expression analysis correlates to the clinical and biochemical phenotypes in East Asians. The molecular defects at the PAH gene regulate the in vivo PAH activities and clinical manifestations.