Russian Journal of Genetics

, Volume 44, Issue 10, pp 1212–1218 | Cite as

Predicting a clinical/biochemical phenotype for PKU/MHP patients with PAH gene mutations

  • J. Kasnauskienė
  • L. Cimbalistienė
  • V. Kučinskas
Experimental Articles


Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). In this study, a total of 218 independent PAH chromosomes (109 unrelated patients with PKU residing in Lithuania) were investigated. All 13 exons of the PAH gene of all PKU probands were scanned for DNA alterations by denaturing gradient gel electrophoresis (DGGE). In the cases of a specific DGGE pattern recognized, mutations were identified by direct fluorescent automated sequencing or by restriction enzyme digestion analysis of relevant exons. Twenty-five different PAH gene mutations were identified in Lithuania. We estimated a connection between individual PAH locus mutations and biochemical and metabolic phenotypes in patients in whom the mutant allele acts on its own, i.e., in functionally hemizygous patients and using the assigned value (AV) method to determine the severity of both common and rare mutant alleles, as well as to check a model to predict the combined phenotypic effect of two mutant PAH alleles.


Phenylalanine Hydroxylase Molecular Genetic Testing R408W Mutation Restriction Enzyme Digestion Analysis Human Phenylalanine Hydroxylase 
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  1. 1.
    Scriver, C.R., Kaufman, S., and Woo, S.L.C., The Phenylalaninemias, The Metabolic and Molecular Bases of Inherited Disease, Scriver, C.R., Beaudet, A.L., Valle. D., and Sly, W., New York: McGraw-Hill, 2001, pp. 15–1077.Google Scholar
  2. 2.
    Kaufman, S., The Phenylalanine Hydroxylating System, Adv. Enzymol., 1993, vol. 67, pp. 77–264.PubMedGoogle Scholar
  3. 3.
    Hufton, S.E., Jennings, I.G., and Cotton, R.G., Structure and Function of the Aromatic Amino Acid Hydroxylases, Biochem. J., 1995, vol. 311, pp. 353–366.PubMedGoogle Scholar
  4. 4.
    Kappock, T.J. and Caradonna, J.P., Pterin-Dependent Amino Acid Hydroxylases, Chem. Rev., 1996, vol. 96, pp. 2659–2756.PubMedCrossRefGoogle Scholar
  5. 5.
    Erlandsen, H., Fusetti, F., Martinez, A., et al., Crystal Structure of the Catalytic Domain of Human Phenylalanine Hydroxylase Reveals the Structural Basis for Phenylketonuria, Nature Structural Biol., 1997, vol. 4, p. 995.CrossRefGoogle Scholar
  6. 6.
    Scriver, C.R., Eisensmith, R.C., Woo, S.L., and Kaufman, S., The Hyperphenylalaninemias of Man and Mouse, Annu. Rew. Gene, 1994, vol. 28, pp. 141–165.CrossRefGoogle Scholar
  7. 7.
    Online Mendelian Inheritance in Man (OMIM), URL:
  8. 8.
    Scriver, C.R. and Nowacki, P.M., PAHdb: Phenylalanine Hydroxylase Locus Database, available from URL:, update, 1996.
  9. 9.
    Güttler, F., Hyperphenylalaninemia: Diagnosis and Classification of the Various Types of Phenylalanine Hydroxylase Deficiency, Acta Pediatr. Scand. Suppl., 1980, vol. 280, pp. 1–80.Google Scholar
  10. 10.
    Scriver, C.R. and Waters, P.J., Monogenic Traits Are not Simple, Trends Genet., 2001, vol. 15, pp. 267–272.CrossRefGoogle Scholar
  11. 11.
    Guldberg, P., Rey, F., Zschocke, J., et al., A European Multicenter Study of Phenylalanine Hydroxylase Deficiency: Classification of 105 Mutations and a General System for Genotype-Based Prediction of Metabolic Phenotype, Am. J. Hum. Genet., 1998, vol. 63, pp. 71–79.PubMedCrossRefGoogle Scholar
  12. 12.
    Kayaalp, E., Treacy, E., and Waters, P.J., et al., Human Phenylalanine Hydroxylase Mutations and Hyperphenylalaninemia Phenotypes: Metanalysis of Genotype-Phenotype Correlation, Am. J. Hum. Genet., 1997, vol. 61, pp. 1309–1317.PubMedCrossRefGoogle Scholar
  13. 13.
    Jennings, I.G., Cotton, R.G., and Kobe, B., Structural Interpretation of Mutations in Phenylalanine Hydroxylase Protein Aids in Identifying Genotype-Phenotype Correlations in Phenylketonuria, Europ. J. Hum. Genet., 2000, vol. 8, pp. 683–696.PubMedCrossRefGoogle Scholar
  14. 14.
    Giannattasio, S., Jurgelevičius, V., Lattanzio, P., et al., Phenylketonuria Mutations and the Linked Haplotypes in the Lithuanian Population: Origin of the Most Common R408W Mutation, Hum. Hered., 1997, vol. 47, pp. 155–160.PubMedCrossRefGoogle Scholar
  15. 15.
    Zschocke, J. and Hoffmann, G.F., Phenylketonuria Mutations in Germany, Hum. Genet., 1999, vol. 104, pp. 390–398.PubMedCrossRefGoogle Scholar
  16. 16.
    Flatmak T., Stevens R.C. Structural Insight into the Aromatic Amino Acid Hydroxylases and Their Disease-Related Mutant Forms, Chem. Rev., 1999, vol. 99, pp. 2137–2160.CrossRefGoogle Scholar

Copyright information

© MAIK Nauka 2008

Authors and Affiliations

  • J. Kasnauskienė
    • 1
  • L. Cimbalistienė
    • 1
  • V. Kučinskas
    • 1
  1. 1.Department of Human and Medical GeneticsVilnius UniversityVilniusLithuania

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