Founder effect of a prevalent phenylketonuria mutation in the Oriental population.

Abstract

A missense mutation has been identified in the human phenylalanine hydroxylase [PAH; phenylalanine 4-monooxygenase; L-phenylalanine, tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1] gene in a Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that "northern Mongoloids" represented a founding population in Asia. Our results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity

“…Studies on disease genes, such as phenylalanine hydroxylase (PAH) for phenylketonuria (Lo et al 1993;Wang et al 1991) and citrin (SLC25A13) for adult-onset type II citrillinemia (Lu et al 2005), were consistent with the findings of Zhao and Lee. A founder mutation of classical hyperphenylalanemia, p.R413P, was mostly present in Chinese populations north of the Yangtze River (Wang et al 1991), while a common mutation of SLC25A13, c.851_854del, only occurred in Chinese populations south of the Yangtze River (Lu et al 2005). A complete description of early populations must allow, therefore, the possibility of admixture of Chinese populations across the Yangtze River.…”

Biochemical investigation of young hospitalized Chinese children: Results over a 7-year period

“…Interestingly, the occurrence of PKU in the Chinese in Singapore, who probably originated from southern China, is reputed to be rare, although the actual incidence is unknown [Tan et al, 1995]. Meanwhile, an R413P mutation in the phenylalanine hydroxylase gene, which is caused by a G→C substitution at the second base of codon 413 and leads to classic phenylketonuria, was shown to be carried by a founder effect in the northern Chinese but not the southern Chinese [Wang et al, 1991]. These findings support a historical belief that the northern and southern Chinese are of two different origins, the former being descendants of an indigenous population in the Yellow River basin, and the latter the offsprings of ancient settlers in the Yangtze River valley [Zhao and Lee, 1989].…”

Mutation analysis of the phenylalanine hydroxylase gene and its clinical implications in two Japanese patients with non-phenylketonuria hyperphenylalaninemia

“…1 Identification of missense mutations in the PAH gene by the PCR cycle sequencing method. Primers used for PCR amplification and sequencing are described by Wang et al (1991aWang et al ( , 1991c. A R241C and R243Q mutations in exon 7 of patients A and B.…”

“…The coding sequence and flanking region of each exon were scanned for mutations by polymerase chain reaction (PCR)-single strand conformation polymorphism. The nucleotide sequence of each set of primers was described previously (Wang et al , 1991a(Wang et al , 1991b(Wang et al , 1991c(Wang et al , 1992Lin et al 1992;Takarada et al 1994). The exonic regions containing a variant sequence were subjected to direct sequencing analysis.…”

“…Presently, more than 20PKU mutations among Japanese and other Oriental populations have been reported (Wang et al , 1991a(Wang et al , 1991b(Wang et al , 1991c(Wang et al , 1992Lin et al 1992;Okano et al 1994aOkano et al , 1994b; Takarada et al…”