Phenylketonuria (PKU) is an inborn error of metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). We characterized the PAH mutations of 79 independent Korean patients with PKU or hyperphenylalaninemia. PAH nucleotide sequence analysis revealed 39 different mutations, including ten novel mutations. The novel mutations consisted of nine missense mutations (P69S, G103S, N207D, T278S, P281A, L293M, G332V, S391I, and A447P) and a novel splice site variant (IVS10À3C>G). R243Q, IVS4À1G>A, and E6À96A>G were the most prevalent mutations, as they accounted for 32% of the total mutant alleles in this study. Although some common characteristics of allele frequency and distribution were identified among oriental populations, several distinctive characteristics were revealed in Korean patients. Although the R413P allele is the most prevalent form (30.5%) in Japanese, we detected it in only five chromosomes from 158 independent chromosomes (3.2%). The A259T allele, which has not yet been found in oriental populations, was frequently found in this study. We also observed that tetrahydrobiopterin (BH 4 ) responsiveness was associated with specific genotypes (R53H, R241C, and R408Q), suggesting there are some correlations between phenotype and genotype.
Homocystinuria is an autosomal recessive inborn error of metabolism that is most often caused by mutation in the cystathionine beta-synthase (CBS) gene. Patients may develop serious clinical manifestations such as lens dislocation, mental retardation, osteoporosis, and atherothrombotic vascular disease. Over 100 mutations have been reported, but so far, none have been reported in Korea. Mutation analysis of the CBS gene in six Korean patients with homocystinuria was performed by direct sequencing. Eight mutations were identified, including four known mutations (T257M, R336C, T353M, and G347S) and four novel mutations (L154Q, A155V, del234D, and A288T). All patients were compound heterozygotes. To characterize these mutations, normal or mutated forms of CBS were cloned into pcDNA3.1 expression vector followed by transfection into mammalian cells for transient expression. Whereas the expression levels of mutant proteins were comparable to that of normal control, enzyme activities of all the mutant forms were significantly decreased. In addition, a novel single nucleotide polymorphism, R18C, was identified, which showed onethird to two-thirds the enzyme activity of wild type and 1% of the allele frequency in normal control. The spectrum of mutations observed in Korean patients bears less resemblance to those observed in Western countries.
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