In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: Characterization of seven common mutations View Full Text


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Article Info

DATE

1995-07

AUTHORS

Per Guldberg, Ingrid Mikkelsen, Karen F. Henriksen, Hans C. Lou, Flemming Güttler

ABSTRACT

Mutations in the gene encoding phenylalanine hydroxylase (PAH) cause persistent hyperphenylalaninaemia. To date, more than 200 point mutations and microdeletions have been characterized. Each mutation has a particular quantitative effect on enzyme activity and recessive expression of different mutant alleles results in a marked interindividual heterogeneity of metabolic and clinical phenotypes. In this paper we demonstrate how a simple clinical test can be used to evaluate the correlation between mutation genotype and phenylalanine metabolism. In hyperphenylalaninaemic patients with known PAH mutation genotype, we have investigated phenylalanine turnover in vivo by measuring the ability to eliminate a test dose of L-phenylalanine. All patients could be considered functionally hemizygous for one of their mutant alleles by carrying on the other allele a mutation that is known to completely abolish PAH activity and encode a peptide with no immunoreactivity. Seven mutations (R408W, IVS-12nt1, R261Q, G46S, Y414C, A104D, and D415N) were characterized by oral phenylalanine loading, each mutation being represented by at least three patients. The elimination profile determined for a 3-day period provides a measure to compare residual activity of the mutant proteins and to assign each mutation to a particular metabolic phenotype. The established relation between genotype and phenotype may enable prediction of the severity of the disease by genotype determination in the newborn period. This will aid in the management of hyperphenylalaninaemia and may improve prognosis. CONCLUSION: The possibility of predicting the residual enzyme activity by DNA analysis performed already in the newborn period allows the prompt implementation of a diet that is adjusted to the degree of PAH deficiency. This may improve management and prognosis of hyperphenylalaninaemia. More... »

PAGES

551-556

References to SciGraph publications

  • 1969-07. Detection of Heterozygotes for Phenylketonuria by Column Chromatography and Discriminatory Analysis in PEDIATRIC RESEARCH
  • 1994-05. Relation between phenylalanine hydroxylase genotypes and phenotypic parameters of diagnosis and treatment of hyperphenylalaninaemic disorders in JOURNAL OF INHERITED METABOLIC DISEASE
  • 1956-12. Detection by Phenylalanine Tolerance Tests of Heterozygous Carriers of Phenylketonuria in NATURE
  • 1987-11. Characterization of β-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA in NATURE
  • 1993-02. Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients in EUROPEAN JOURNAL OF PEDIATRICS
  • 1977. Phenylketonuria: Biochemical Mechanisms in ADVANCES IN NEUROCHEMISTRY
  • 1990. Phenylketonuria and Hyperphenylalaninemia in INBORN METABOLIC DISEASES
  • 1987-05. An ammo-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2 in NATURE
  • 1979-01. Kinetics of Phenylalanine Disappearance after Intravenous Load in Phenylketonuria and Its Genetic Variants in PEDIATRIC RESEARCH
  • 1981-12. In Vivo residual activities of the phenylalanine hydroxylating system in phenylketonuria and variants in JOURNAL OF INHERITED METABOLIC DISEASE
  • 1991-03. A prevalent missense mutation in Northern Europe associated with hyperphenylalaninaemia in EUROPEAN JOURNAL OF PEDIATRICS
  • 1986-08. Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria in NATURE
  • 1991-05. Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation in EUROPEAN JOURNAL OF PEDIATRICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/bf02074833

    DOI

    http://dx.doi.org/10.1007/bf02074833

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037023851

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/7556322


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