Molecular Analysis of Phenylketonuria in East Asians

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Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). More than 100 different mutations have been identified worldwide and it has be revealed that PKU is a highly heterogeneous disorder, I performed the molecular analysis of PKU in East Asia.I have characterized 60% of all PKU alleles in East Asians 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. I found different mutations between Caucasians and East Asians, and therefore PKU mutations have occurred after racial 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.Illegitimate transcription is useful for the detection of several PKU mutations, since PAH is expressed in the liver only. I identified two missense mutations (R241C,R408Q) by PAH cDNA analysis and characterized a splicing muation caused by a nonsense mutation (Y356X) and a deletion of 10 kb of genomic DNA by analysis of both PAH cDNA and genomic DNA at the PAH locus.As for the DNA polymorphisms, RFLP haplotypes and VNTR were not useful for DNA diagnosis. Short tandem repeat system showed heterozygosity of 70%, which would permit the prenatal diagnosis in 15 of the 19 PKU families. The high degree of polymorphisms and Mendelian segregation in the STR system is useful for the prenatal diagnosis in Japanese families with PKU.