Advertisement

Journal of Inherited Metabolic Disease

, Volume 13, Issue 5, pp 739–750 | Cite as

Heterogeneity of phenylketonuria at the clinical, protein and DNA levels

  • R. G. H. Cotton
Article

Summary

The cloning of the phenylalanine hydroxylase gene and cDNA has potentially allowed the complete characterization of patients with phenylketonuria and already many mutations have been defined. Parents of patients now have the option of prenatal diagnosis. The 18 mutations defined so far indicate enormous heterogeneity not only within particular populations but also between populations. These mutations give little indication as to the locations of the amino acid residues important in enzyme function but one-third of the mutations are in exon 7 which may be indicating the importance of the region coded by this exon in the protein.

Keywords

Public Health Internal Medicine Amino Acid Residue Metabolic Disease Phenylalanine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abadie, V., Lyonnet, S., Maurin, N., Berthelon, M., Caillaud, C., Giraud, F., Mattei, J. F., Rey, J., Rey, F. and Munnich, A. CpG dinucleotides are mutation hot spots in phenylketonuria.Am. J. Hum. Genet. 45 (1989) Abstract 661Google Scholar
  2. Aulehla-Scholz, C., Vorgerd, M., Sautter, E., Leupold, D., Mahlmann, R., Ullrich, K., Olek, K. and Horst J. Phenylketonuria: distribution of DNA diagnostic patterns in German families.Hum. Genet. 78 (1988) 353–355Google Scholar
  3. Avigad, S., Kleiman, S., Cohen, B. E., Orgad, S., Holtzer, L., Schwartz, G., Gazit, E., Lyonnet, S., Woo, S. L. C. and Shiloh, Y. Molecular population genetics of phenylketonuria in Israel.Am. J. Hum. Genet. 43 (1988) Abstract 838Google Scholar
  4. Chakraborty, R., Lidsky, A. S., Daiger, S. P., Güttler, F., Sullivan, S., DiLella, A. G. and Woo, S. L. C. Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria.Hum. Genet. 76 (1987) 40–46Google Scholar
  5. Chen, S.-H., Hsiao, K.-J., Lin, L.-H., Liu, T.-T., Tang, R.-B. and Su, T.-S. Study of restriction fragment length polymorphisms at the human phenylalanine hydroxylase locus and evaluation of its potential application in prenatal diagnosis of phenylketonuria in Chinese.Hum. Genet. 81 (1989) 226–230Google Scholar
  6. Cotton, R. G. H. Inborn errors of pterin metabolism. In: Blakley, R. L. and Whitehead, V. M. (eds),Pterins and Folates, Nutritional Pharmacologic and Physiological Aspects of Folates and Pterins, vol. 2, John Wiley, New York 1986, pp. 359–412Google Scholar
  7. Cotton, R. G. H., Dahl, H. H. M., Mercer, J. F. B., Jennings, I., Haan, E. A., Chow, C. W., Danks, D. M. and Morgan, F. J. Molecular biology of phenylalanine hydroxylase.J. Inher. Metab. Dis. 9 (1986) 206–208Google Scholar
  8. Daiger, S. P., Chakraborty, R., Güttler, F., Lidsky, A. S., Koch, R. and Woo, S. L. C. Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria.Lancet 1 (1986) 229–323Google Scholar
  9. Dianzani, I., Farinasso, L., Fortina, P., Camaschella, C., Ponzone, R., Dahl, H. H. M., Cotton, R. G. H. and Ponzone, A. RFLP of the phenylalanine hydroxylase (PAH) gene in the Italian population.J. Inher. Metab. Dis. 12 (1989a) 162–165Google Scholar
  10. Diazani, I., Camaschella, C., Saglio, G., Ferrero, G. B., Romeo, G., Devoto, M., Romano, C., Cerone, R., Giovannini, M., Riva, E., Trefz, F. K., Lichter-Konecki, U. and Woo, S. L. C. Haplotype distribution and molecular defects of PKU in Italy. Abstract, SSIEM, London, 1989bGoogle Scholar
  11. Di Lella, A. G., Ledley, F. D., Rey, F., Munnich, A. and Woo, S. L. C. Detection of phenylalanine hydroxylase messenger RNA in liver biopsy samples from patients with phenylketonuria.Lancet 1 (1985) 160–161Google Scholar
  12. DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J. and Woo, S. L. C. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene.Biochemistry 25 (1986a) 743–749Google Scholar
  13. DiLella, A. G., Marvit, J., Lidsky, A. S., Güttler, F. and Woo, S. L. C. Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria.Nature 322, (1986b) 799–803Google Scholar
  14. DiLella, A. G., Marvit, J., Brayton, K. and Woo, S. L. C. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2.Nature 327 (1987) 333–336Google Scholar
  15. DiLella, A. G., Huang, W.-M. and Woo, S. L. C. Screening for phenylketonuria mutations by DNA amplification with the polymerase chain reaction.Lancet 1 (1988) 497–499Google Scholar
  16. Forrest, S. M., Howells, D. W., Dahl, H.-H. and Cotton, R. G. H. Use of the chemical cleavage method to detect mutations causing phenylketonuria and dihydropteridine reductase deficiency.Am. J. Hum. Genet. 45 (1989) Abstract 186Google Scholar
  17. Güttler, F., Ledley, F. D., Lidsky, A. S., DiLella, A. G., Sullivan, S. E. and Woo, S. L. C. Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria.J. Pediatr. 110 (1987) 68–71Google Scholar
  18. Heimlich, J., Kopietz-Schulte, E., Olek, K. and Bartholomè. Mutant phenylalanine hydroxylase characterized by the immunoblotting technique.Eur. J. Pediatr. 143 (1985) 243Google Scholar
  19. Hertzberg, M., Jahromi, K., Ferguson, V., Dahl, H. H. M., Mercer, J., Mickleson, K. N. P. and Trent, R. J. Phenylalanine hydroxylase gene haplotypes in Polynesians; evolutionary origins and absence of alleles associated with severe phenylketonuria.Am. J. Hum. Genet. 44 (1989) 382–387Google Scholar
  20. Hofman, K., Valle, D., Kazazian, H. and Snyderman, S. Haplotype analysis of the phenylalanine hydroxylase (PH) gene in US Blacks with phenylketonuria (PKU).Am. J. Hum. Genet. 41 (1987) Abstract 761Google Scholar
  21. Horst, J., Aulehla-Scholz, C. and Dworniczak, B. Phenylketonuria: Identification of a new frequent mutation in the phenylalanine hydroxylase gene.Am. J. Hum. Genet. 45 (1989) Abstract 766Google Scholar
  22. Hsia, D. Y., O'Flynn, M. E. and Berman, J. L. Atypical PKU with borderline or normal intelligence.Am. J. Dis. Child. 116 (1968) 143–157Google Scholar
  23. John, S., Rozen, R., Laframboise, R., Laberge, C. and Scriver, C. R. RFLP haplotypes associated with hyperphenylalaninemia alleles at the phenylalanine hydroxylase (PAH) locus in French-Canadians.Am. J. Hum. Genet. 43 (1988) Abstract 860Google Scholar
  24. John, S. W. M., Rozen, R., Laframboise, R., Laberge, C. and Scriver, C. R. Novel (codon 1) mutation and extensive genetic diversity at the phenylalanine hydroxylase (PAH) locus in French Canadians.Am. J. Hum. Genet. 45 (1989) Abstract 776Google Scholar
  25. Kwok, S. C. M., Ledley, F. D., DiLella, A. G., Robson, K. J. H. and Woo, S. L. C. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase.Biochemistry 24 (1985) 556–561Google Scholar
  26. Ledley, F. D., Koch, R., Jew, K., Beaudet, A., O'Brien, W. E., Bartos, D. P. and Woo, S. L. C. Phenylalanine hydroxylase expression in liver of a fetus with phenylketonuria.J. Pediatr. 113 (1988) 463–468Google Scholar
  27. Lichter-Konecki, U., Konecki, D. S., DiLella, A. G., Brayton, K., Marvit, J., Hahn, T. M., Trefz, K. F. and Woo, S. L. C. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene.Biochemistry 27 (1988a) 2881–2885Google Scholar
  28. Lichter-Konecki, U., Schlotter, M., Konecki, D. S., Labeit, S., Woo, S. L. C. and Trefz, K. Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population.Hum. Genet. 78 (1988b) 347–352Google Scholar
  29. Lichter-Konecki, U., Schlotter, M., Yaylak, C., Özgüc, M., Coskun, T., Özalp, I., Wendel, U., Batzler, U., Trefz, F. K. and Konecki, D. DNA haplotype analysis at the Turkish phenylalanine hydroxylase locus.Hum. Genet. 81 (1989) 373–376Google Scholar
  30. Lidsky, A. S., Ledley, F. D., DiLella, A. G., Kwok, S. C. M., Daiger, S. P., Robson, K. J. H. and Woo, S. L. C. Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria.Am. J. Hum. Genet. 37 (1985a) 619–634Google Scholar
  31. Lidsky, A. S., Güttler, F. and Woo, S. L. C. Prenatal diagnosis of classic phenylketonuria by DNA analysis.Lancet 1 (1985b) 549–551Google Scholar
  32. Lyonnet, S., Caillund, C., Rey, F., Berthelon, M., Frezal, J., Rey, J. and Munnich, A. Guthrie cards for detection of point mutations in phenylketonuria.Lancet 2 (1988) 507Google Scholar
  33. Lyonnet, S., Caillund, C., Rey, F., Berthelon, M., Frezal, J., Rey, J. Munich, A. Molecular genetics of phenylketonuria in Mediterranean countries: characterization of the first mutation responsible for partial phenylalanine hydroxylase deficiency.Am. J. Hum. Genet. 44 (1989) 511–517Google Scholar
  34. Moore, S. D., Huang, W. M., Koch, R., Snyderman, S. and Woo, S. L. C. Molecular population genetics of phenylketonuria in the United States and potential for carrier screening.Am. J. Hum. Genet. 43 (1988) Abstract 90Google Scholar
  35. O'Flynn, M. E., Holtzman, N. A., Blaskovics, M., Azen, C. and Williamson, M. L. The diagnosis of phenylketonuria.Am. J. Dis. Child. 134 (1980) 769–774Google Scholar
  36. Okano, Y., Wang, T., Eisensmith, R. C., Gitzelmann, R. and Woo, S. L. C. Mis-sense mutation associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene.Am. J. Med. Genet. B2 (1988a) Supp.Google Scholar
  37. Okano, Y., Wang, T., Eisensmith, R. C. and Woo, S. L. C. PKU mutations among Caucasians.Am. J. Hum. Genet. 45 (1989b) Abstract 828Google Scholar
  38. Reiss, O., Michel, A., Speer, A., Cobet, G. and Coutelle, Ch. Introduction of genomic diagnosis of classical phenylketonuria to the health care system of the German Democratic Republic.Clin. Genet. 32 (1987) 209–215Google Scholar
  39. Reiss, O., Michel, A., Speer, A., Meiske, W., Cobet, G. and Coutelle, C. Linkage disequilibrium between RFLP haplotype 2 and the affected PAH allele in PKU families from the Berlin area of the German Democratic Republic.Hum. Genet. 78 (1988) 343–346Google Scholar
  40. Reiss, O., Michel, A., Berger, W., Nurnberg, P., Epplen, J. T., Speer, A. and Coutelle, C. RFLP-discordance within the phenylalanine hydroxylase locus.Hum. Genet. 83 (1989) 199–201Google Scholar
  41. Rey, F., Berthelon, M., Caillad, C., Lyonnet, S., Abadie, V., Blandin-Savoja, F., Feingold J., Saudubray, J.-M., Frèzal, Munnich, A. and Rey, J. Clinical and molecular heterogeneity of phenylalanine hydroxylase.Am. J. Hum. Genet. 43 (1988) 914–921Google Scholar
  42. Robson, K. J. H., Chandra, T., MacGillvray, R. T. A. and Woo, S. L. C. Polysome immunoprecipitation of phenylalanine hydroxylase mRNA from rat liver and cloning of its cDNA.Proc. Natl. Acad. Sci. USA 79 (1982) 4701–4705Google Scholar
  43. Robson, K. J. H., Beattie, W., James, R. J., Cotton, R. G. H., Morgan, F. J. and Woo, S. L. C. Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA clones.Biochemistry 23 (1984) 5671Google Scholar
  44. Scriver, C. R. and Clow, C. L. Phenylketonuria: Epitome of human biochemical genetics.N. Engl. J. Med. 303 (1980) 1336–1342Google Scholar
  45. Speer, A., Dahl, H. H., Reiss, O., Cobet, G., Hanke, R., Cotton, R. G. H. and Coutelle, Ch. Typing of families with classical phenylketonuria using three alleles of the HindIII linked restriction fragment polymorphism, detectable with a phenylalanine hydroxylase cDNA probe. Family typing for PKU by linked HindIII RFLP.Clin. Genet. 29 (1986a) 491–495Google Scholar
  46. Speer, A., Bollman, R., Michel, A., Neumann, R., Bommer, C. H., Hanke, R., Reiss, O., Cobet, G. and Coutelle, Ch. Prenatal diagnosis of classical phenylketonuria by linked restriction fragment length polymorphism analysis.Prenatal Diag. 6 (1986b) 447–450Google Scholar
  47. Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L. and Brown, M. S. (eds),The Metabolic Basis of Inherited Disease, 5th edn., McGraw-Hill, New York, 1983Google Scholar
  48. Stuhrmann, M., Reiss, O., Monch, E. and Kurdoglu, G. Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria families.Clin. Genet. 36 (1989) 117–121Google Scholar
  49. Sullivan, S. E., Moore, S. D., Connor, J. M., King, M., Cockburn, F., Steinmann, B., Gitzelmann, R., Daiger, S. P. and Woo, S. L. C. Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland.Am. J. Hum. Genet. 44 (1989) 652–659Google Scholar
  50. Svensson, B., Andersso, B. and Hagenfeldt, L. Two mutations eliminating restriction enzyme recognition sites at the phenylalanine hydroxylase locus segregate with the disease state of phenylketonuria. Abstract, SSIEM, London, 1989Google Scholar
  51. Trefz, F. K., Lichter-Konecki, U., Konecki, D. S., Schlotter, M. and Bickel, H. PKU and Non-PKU hyperphenylalaninemia: Differentiation, indication for therapy and therapeutic results.Acta Paediatr. Jpn. 30 (1988) 397–404Google Scholar
  52. Trefz, F. K., Yoshino, M., Aengeneyndt, F., Schmidt-Mader, B., Lichter-Konechi, U. and Konecki, D. S. Restriction fragment polymorphism (RFLP)-patterns in Japanese PKU-families: new polymorphism for the mutant phenylalanine hydroxylase gene. Abstract PO18, SSIEM, London, 1989Google Scholar
  53. Tyfield, L. A., Meredith, A. L., Osborn, M. J. and Harper, P. S. Identification of the haplotype pattern associated with the mutant PKU allele in the Gypsy population of Wales.J. Med. Genet. 26 (1989) 499–503Google Scholar
  54. Verelst, P., Denis, C., Rossius, M., Allaer, D., Francois, B., Martial J. and Dahl, H. Restriction fragment length polymorphism in the phenylalanine hydroxylase locus in the Belgian population. Abstract, SSIEM, London, 1988Google Scholar
  55. Wang, T., Okano, Y., Eisensmith, R. C., Zeng, Y. T., Huang, S. Z., Lo, W. H. Y. and Woo, S. L. C. Molecular genetics of PKU in orientals.Am. J. Hum. Genet. 45 (1989a) Abstract 898Google Scholar
  56. Wang, T., Okano, Y., Eisensmith, R., Huang, S.-Z., Zeng, Y.-T., Lo, W. H. Y. and Woo, S. L. C. Molecular genetics of phenylketonuria in orientals: linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene.Am. J. Hum. Genet. 45 (1989b) 675–680Google Scholar
  57. Woo, S. L. C. Collation of RFLP haplotypes at the human phenylalanine hydroxylase (PAH) locus.Am. J. Hum. Genet. 43 (1988) 781–783Google Scholar
  58. Woo, S. L. C. Molecular basis and population genetics of phenylketonuria.Biochemistry 28 (1989) 1–6Google Scholar

Copyright information

© SSIEM and Kluwer Academic Publishers 1990

Authors and Affiliations

  • R. G. H. Cotton
    • 1
  1. 1.Olive Miller Protein Laboratory, The Murdoch InstituteRoyal Children's HospitalMelbourneAustralia

Personalised recommendations