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Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency


Zurflüh, M R; Zschocke, J; Lindner, M; Feillet, F; Chery, C; Burlina, A; Stevens, R C; Thöny, B; Blau, N (2008). Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Human Mutation, 29(1):167-175.

Abstract

Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH4)-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 BH4-responsiveness may be predicted from the corresponding genotypes. Data from BH4 loading tests indicated an incidence of BH4-responsiveness of 440% in the general PKU population and 480% in mild PKU patients. The current project entailed genotype analysis of 315 BH4-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 ~47%), presumed to be associated with BH4-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in 45% of BH4-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH4-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 BH4-responsiveness was higher than prevalence data obtained from BH4 loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH4-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient’s genotype.

Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH4)-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 BH4-responsiveness may be predicted from the corresponding genotypes. Data from BH4 loading tests indicated an incidence of BH4-responsiveness of 440% in the general PKU population and 480% in mild PKU patients. The current project entailed genotype analysis of 315 BH4-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 ~47%), presumed to be associated with BH4-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in 45% of BH4-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH4-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 BH4-responsiveness was higher than prevalence data obtained from BH4 loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH4-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient’s genotype.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2008
Deposited On:23 Oct 2008 07:24
Last Modified:05 Apr 2016 12:30
Publisher:Wiley-Blackwell
ISSN:1059-7794
Publisher DOI:10.1002/humu.20637
PubMed ID:17935162
Permanent URL: http://doi.org/10.5167/uzh-4336

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