The molecular basis of phenylketonuria in Koreans

Lee, Dong Hwan; Koo, Soo Kyung; Lee, Kwang Soo; Yeon, Young Joo; Oh, Hyun Joo; Kim, Sang Wun; Lee, Sook Jin; Kim, Sung Soo; Lee, Jong Eun; Jo, Inho; Jung, Sung Chul

doi:10.1007/s10038-004-0197-5

Cited by 52 publications

(58 citation statements)

References 13 publications

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“…The p.R408W mutation was the predominant mutation in Ireland, Latvia and Lithuania (O'Donnell et al 2002;Kasnauskiene et al 2003;Pronina et al 2003), whereas c.1315+1G>A had the highest frequency in England, Germany and Denmark (Guldberg et al 1993;Aulehla-Scholz and Heilbronner 2003;Zschocke 2003). Other examples of region-specific mutations include c.1066-11G>A from Mediterranean regions and p.R243Q and p.R413P from Asia (Chien et al 2004;Lee et al 2004;Song et al 2005). The low incidence of these mutations in our cohort reflects the high cultural diversity in NSW, Australia (Australian Bureau of Statistics 2012).…”

Section: Discussionmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c. 163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified.A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH 4 ), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH 4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH 4 .

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Section: Discussionmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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“…1 Mass screening of newborns for PKU is performed in developed countries and patients show a wide spectrum of clinical severity. The incidence of PKU in Japan is 1/120 000, 2 which is lower than in Caucasians (1/10 000), 3 Chinese (1/18 000) 4 and Korean (1/41 000) 5 populations. The diagnosis of PKU is based on high phenylalanine levels and absence of tetrahydrobiopterin (BH 4 ) deficiency, rather than on hepatic PAH activity.…”

Section: Introductionmentioning

confidence: 94%

“…The distribution and frequency of PKU mutations were compared among Northern Chinese, 33 Korean, 5 Taiwanese 34 and Japanese populations. Figure 2 shows PKU mutations with 45% frequency in at least one of these countries.…”

Section: Comparison Among East Asian Countriesmentioning

confidence: 99%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g4a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH 4 ) responsiveness. The frequency of BH 4 responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH 4 therapy, and genetic counseling in East Asia.

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“…In a previous study, only 86% of the mutant alleles were identified by sequence analysis of the entire PAH coding region, suggesting that large deletions or duplication are frequent causes of PKU in Koreans (Lee et al, 2004). To elucidate this hypothesis, we performed both sequencing and gene dosage analyses of the PAH gene in 33 unrelated Korean PKU patients.…”

Section: Introductionmentioning

confidence: 96%

Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria

Lee

Kim

et al. 2008

Exp Mol Med

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Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify ~14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.

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The molecular basis of phenylketonuria in Koreans

Cited by 52 publications

References 13 publications

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria

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