Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Hum Mutat. 2008 Jan;29(1):167-75. doi: 10.1002/humu.20637.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopterins / analogs & derivatives*
  • Biopterins / metabolism
  • Biopterins / therapeutic use
  • China
  • Europe
  • Gene Expression Regulation, Enzymologic
  • Gene Frequency
  • Genetics, Population
  • Genotype
  • Humans
  • Korea
  • Models, Molecular
  • Mutation
  • Phenylalanine Hydroxylase / deficiency*
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / drug therapy*
  • Phenylketonurias / genetics*
  • Phenylketonurias / metabolism

Substances

  • Biopterins
  • Phenylalanine Hydroxylase
  • sapropterin