1. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.
- Author
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Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, and Blau N
- Subjects
- Biopterins metabolism, Biopterins therapeutic use, China, Europe, Gene Expression Regulation, Enzymologic, Gene Frequency, Genetics, Population, Genotype, Humans, Korea, Models, Molecular, Mutation, Phenylketonurias metabolism, Biopterins analogs & derivatives, Phenylalanine Hydroxylase deficiency, Phenylalanine Hydroxylase genetics, Phenylketonurias drug therapy, Phenylketonurias genetics
- Abstract
Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BH(4)-responsiveness may be predicted from the corresponding genotypes. Data from BH(4) loading tests indicated an incidence of BH(4)-responsiveness of >40% in the general PKU population and >80% in mild PKU patients. The current project entailed genotype analysis of 315 BH(4)-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average approximately 47%), presumed to be associated with BH(4)-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH(4)-responsiveness in European populations was calculated to be 55% (range 17-79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype-predicted prevalence of BH(4)-responsiveness was higher than prevalence data obtained from BH(4) loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH(4)-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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