Advertisement

Human Genetics

, Volume 87, Issue 4, pp 377–388 | Cite as

The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations

  • David S. Konecki
  • Uta Lichter-Konecki
Review Article

Summary

The hyperphenylalaninemic disorders of classic phenylketonuria (PKU), mild phenylketonuria, and hyperphenylalaninemia (HPA), result from a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) or its cofactor (tetrahydrobiopterin). Use of the complementary DNA of this enzyme has allowed the establishment of a restriction fragment length polymorphism (RFLP) haplotype-analysis system. This haplotype analysis system provides the means for determination of mutant PAH alleles in most affected families and is the basis for mutational analysis of the PKU locus. This review is focused on two major areas of current PKU research: (1) the use of DNA haplotype analysis in the study of the population genetics of PAH deficiency, and (2) the study of genotypes, and their various combinations, as a means of explaining and predicting the phenotypic variability observed for the disorders of PAH deficiency.

Keywords

Restriction Fragment Length Polymorphism Population Genetic Haplotype Analysis Major Area Hepatic Enzyme 
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 JF, Rey J, Rey F, Munnich A (1989) CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics 5:963–939Google Scholar
  2. Antonarkis SE, Orkin SH, Kazazian HH, Goff SC, Boehm CD, Waber PG, Sexton JP, Ostrer H, Fairbanks VF, Chakravarti A (1982) Evidence for multiple origins of the β E-globin gene in Southeast Asia. Proc Natl Acad Sci USA 79:6608–611Google Scholar
  3. Aoki K, Wada Y (1988) Outcome of the patients detected by newborn screening in Japan. Acta Paediatr 30:429–434Google Scholar
  4. Apold J, Eiken HG, Odland E, Fredriksen A, Bakken A, Lorens JB, Boman H (1990) A termination prevalent in Norwegian haplotype no. 7 PKU genes. Am J Hum Genet 47:1002–1007Google Scholar
  5. Aulehla-Scholz C, Vorgerd M, Sautter E, Leupold D, Mahlmann R, Ullrich K, Olek K, Horst J (1988) Phenylketonuria: distribution of DNA diagnostic patterns in German families. Hum Genet 78:353–355Google Scholar
  6. Avigad S, Cohen BE, Bauer S, Schwartz G, Frydman M, Woo SLC, Niny Y, Shiloh Y (1990) A single origin of phenylketonuria in Yemenite Jews. Nature 344:168–170Google Scholar
  7. Berthelon M, Caillaud C, Rey F, Labrune P, Meile D, Feingold J, Freazal J, Briard M-L, Farriaux J-P, Guibaud P, Journel H, Maurin N, LeMarrec B, Nivelon J-L, Plauchu H, Saudubray J-M, Tron P, Rey J, Munnich A, Lyonnet S (1991) Spectrum of phenylketonuria mutations in western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus. Hum Genet 86:355–358Google Scholar
  8. Bickel H, Gerrard J, Hickmans EM (1954) The influence of phenylalanine intake on the chemistry and behavior of a phenylketonuric child. Acta Paediatr 43:64–77Google Scholar
  9. Bickel H, Bachmann C, Beckers R (1981) Neonatal mass screening for metabolic disorders. Eur J Pediatr 137:133–139Google Scholar
  10. Caillaud C, Lyonnet S, Melle D, Rey F, Berthelon M, Vilarinho L, Vaz Osorio R, Rey J, Munnich A (1990) Molecular heterogeneity of mutant haplotype 2 alleles in phenylketonuria. Am J Hum Genet 47:A152Google Scholar
  11. Carter CO, Woolf LI (1961) The birthplaces of parents and grandparents of a series of patients with phenylketonuria in southwest England. Ann Hum Genet 25:57–64Google Scholar
  12. Chakraborty R, Lidsky AS, Daiger SP, Güttler F, Sullivan S, DiLella AG, Woo SLC (1987) Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria. Hum Genet 76:40–46Google Scholar
  13. Chen S-H, Hsiao K-J, Lin L-H, Liu T-T, Tang R-B, Su T-S (1989) Study of restriction fragment length polymorphisms at the human phenylalanine hydroxylase locus und evaluation of its potential application in prenatal diagnosis of phenylketonuria in Chinese. Hum Genet 81:226–230Google Scholar
  14. Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155Google Scholar
  15. Daiger SP, Chakraborty R, Reed L, Fekete G, Schuler D, Berenssi G, Nasz I, Brdicka R, Kamaryt J, Pijackova A, Moore S, Sullivan S, Woo SLC (1989) Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU) Am J Hum Genet 45:310–318Google Scholar
  16. Daiger SP, Reed L, Huang SS, Zeng YT, Wang T, Lo WHY, Okano Y, Hase Y, Fukuda Y, Dura T, Tada K, Woo SLC (1989b) Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU) Am J Hum Genet 45:319–324Google Scholar
  17. Dianzani I, Camaschella C, Saglio G, Ferreri GB, Romeo G, Devoto M, Romano C, Cerone R, Giovannini M, Riva E, Trefz FK, Lichter-Konecki U, Woo SLC (1990a) Haplotype distribution and molecular defects of PKU in Italy. J Inher Metab Dis 13:292–294Google Scholar
  18. Dianzani I, Devoto M, Camaschella C, Saglio G, Ferrero GB, Cerone R, Romano C, Romeo G, Giovannini M, Riva E, Angeneydt F, Trefz FK, Okano Y, Woo SLC (1990b) Haplotype distribution and molecular defects at the phenylalanine hydroxylase locus in Italy. Hum Genet 86:69–72Google Scholar
  19. DiLella AG, Kwok SCM, Ledley FD, Marvit J, Woo SLC (1986a) Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry 25:743–749Google Scholar
  20. DiLella AG, Marvit J, Lidsky AS, Güttler F, Woo SLC (1986b) Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria. Nature 322:799–803Google Scholar
  21. DiLella AG, Marvit J, Brayton K, Woo SLC (1987) An amino acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. Nature 327:333–336Google Scholar
  22. Dworniczak B, Aulehla-Scholz C, Horst J (1989) Phenlyketonuria: detection of a frequent haplotype 4 allele mutation. Hum Genet 84:95–96Google Scholar
  23. Dworniczak B, Aulehla-Scholz C, Horst J (1990) Phenylalanine hydroxylase gene: silent mutation uncovers evolutionary origin of different alleles. Clin Genet 38:270–273Google Scholar
  24. Flatz G, Oelbe M, Herrmann H (1984) Ethnic distribution of phenylketonuria in the North German population. Hum Genet 65:396–399Google Scholar
  25. Fölling A (1934) Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezilität. Z Physiol Chem 227:169–176Google Scholar
  26. Güttler F (1984) Phenylketonuria: 50 years since Fölling's discovery and still expanding our clinical and biochemical knowledge. Acta Paediatr Scand 73:705–716Google Scholar
  27. Güttler F, DiLella AG, Ledley FD, Lidsky AS, Kwok SCM, Marvit J, Woo SLC (1987a) Molecular biology of phenylketonuria. Eur J Pediatr 146 [Suppl 1]:A5:A11Google Scholar
  28. Güttler F, Ledley FD, Lidsky AS, DiLella AG, Sullivan SE, Woo SLC (1987b) Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria. J Pediatr 110:68–71Google Scholar
  29. Guthrie R, Susie A (1963) A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32:338–343Google Scholar
  30. Herrmann FH, Wulff K, Wehnert M, Seidlitz G, Güttler F (1988) Haplotype analysis of classical and mild phenotype of phenylketonuria in the German Democratic Republic. Clin Genet 34:176–180Google Scholar
  31. Hertzberg M, Jahromi K, Ferguson V, Dahl HHM, Mercer J, Mickleson KNP, Trent RJ (1989) Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutinary origins and absence of alleles associated with severe phenylketonuria. Am J Hum Genet 44:382–387Google Scholar
  32. Hofman KJ, Antonarakis SE, Missiou-Tsangaraki S, Boehm CD, Valle D (1989) Phenylketonuria in the Greek population: haplotype analysis of the phenylalanine hydroxylase gene and identification of a PKU mutation. Mol Biol Med 6:245–250Google Scholar
  33. Huang S-Z, Ren Z-R, Zeng Y-T, Woo SLC (1991) PAH 399 GTA(Val)→GTT(Val), a new silent mutation found in the Chinese. Hum Genet 86:305–306Google Scholar
  34. Jaruzelska J, Henriksen KF, Güttler F, Riess O, Borski K, Blin N, Slomski R (1991) The codon 408 mutation associated with haplotype 2 is predominant in Polish families with phenylketonuria. Hum Genet 86:247–250Google Scholar
  35. Jervis GA (1947) Studies of phenylpyruvic oligophrenia: the position of the metabolic error. J Biol Chem 169:651–656Google Scholar
  36. Jervis GA (1953) Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidising system. Proc Soc Exp Biol Med 82:514–515Google Scholar
  37. John SWM, Rozen R, Laframboise R, Laberge C, Scriver CR (1989) Novel PKU mutation on haplotype 2 in French-Canadians. Am J Hum Genet 45:905–909Google Scholar
  38. John SWM, Rozen R, Scriver CR, Laframboise R, Laberge C (1990) Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations. Am J Hum Genet 46:970–974Google Scholar
  39. Kaufman S (1957) The enzymatic conversion of phenylalanine to tyrosine. J Biol Chem 226:511–524Google Scholar
  40. Kaufman S (1958) Phenylalanine cofactor in phenylketonuria. Science 128:1506–1508Google Scholar
  41. Kaufman S (1976) Phenylketonuria: biochemical mechanisms. Adv Neurochem 2:1–132Google Scholar
  42. Kazazian HH, Orkin SH, Markham AF, Chapman CR, Youssoufian H, Waber PG (1984) Quantification of the close association between DNA haplotypes and specific β-thalassaemia mutations in Mediterraneans. Nature 310:152–154Google Scholar
  43. Kidd KK (1987) Population genetics of a disease. Nature 327:282–283Google Scholar
  44. Konecki DS, Schlotter M, Trefz FK, Lichter-Konecki U (1991) The identification of two mis-sense mutations at the PAH gene locus in a Turkish patient with phenylketonuria. Hum Genet 87:389–393Google Scholar
  45. Kwok SCM, Ledley FD, DiLella AG, Robson KJH, Woo SLC (1985) Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry 24:556–561Google Scholar
  46. Ledley FD, Grenett HE, DiLella AG, Kwok SCM, Woo SLC (1985) Gene transfer and expression of human phenylalanine hydroxylase. Science 228:77–79Google Scholar
  47. Levy HL (1989) Invited editorial: Molecular genetics of phenylketonuria and its implications. Am J Hum Genet 45:667–670Google Scholar
  48. Lichter-Konecki U, Konecki DS, DiLella AG, Brayton K, Marvit J, Hahn TM, Trefz FK, Woo SLC (1988a) Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene. Biochemistry 27:2881–2885Google Scholar
  49. Lichter-Konecki U, Schlotter M, Konecki DS, Labeit S, Woo SLC, Trefz FK (1988b) Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population. Hum Genet 78:347–352Google Scholar
  50. Lichter-Konecki U, Schlotter M, Yaylak C, Özgüc M, Coskun T, Özalp I, Wendel U, Batzler U, Trefz FK, Konecki D (1989a) DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population. Hum Genet 81:373–376Google Scholar
  51. Lichter-Konecki U, Schlotter M, Trefz FK, Konecki D (1989b) Direct detection of a major PKU mutation in the German population after DNA amplification. Eur J Pediatr 149:120–123Google Scholar
  52. Lichter-Konecki U, Schlotter M, Trefz FK, Konecki DS (1990) Identification of new mutations at the phenylalanine hydroxylase gene locus. 5th International Congress of Inborn Errors of Metabolsim, Asilomar, abstract W4. 4Google Scholar
  53. Lidsky AS, Law ML, Morse HG, Kao F-T, Rabin M, Ruddle FH, Woo SLC (1985a) Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome. Proc Natl Acad Sci USA 82:6221–6225Google Scholar
  54. Lidsky AS, Ledley FD, DiLella AG, Kwok SCM, Daiger SP, Robson KJH, Woo SLC (1985b) Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria. Am J Hum Genet 37:619–634Google Scholar
  55. Lyonnet S, Caillaud C, Rey F, Berthelon M, Frézal J, Rey J, Munnich A (1989) Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am J Hum Genet 44:511–517Google Scholar
  56. Marvit J, DiLella AG, Brayton K, Ledley FD, Robson KJH, Woo SLC (1987) GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria. Nucleic Acids Res 15:5613–5628Google Scholar
  57. Okano Y, Wang T, Eisensmith RC, Woo SLC (1989) PKU mutations among Caucasians. Am J Hum Genet 45:A211Google Scholar
  58. Okano Y, Wang T, Eisensmith RC, Steinmann B, Gitzelmann R, Woo SLC (1990a) Mis-sense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene. Am J Hum Genet 46:18–25Google Scholar
  59. Okano Y, Wang T, Eisensmith RC, Güttler F, Woo SLC (1990b) Recurrent mutation in the human phenylalanine hydroxylase gene. Am J Hum Genet 46:919–924Google Scholar
  60. Okano Y, Güttler F, Wang T, Eisensmith RC, Dasovich MB, Woo SLC (1990c) Correlation of PKU mutant genotypes and clinical phenotypes in Caucasians. Am J Hum Genet 47:A164Google Scholar
  61. Okano Y, Eisensmith R, Güttler E, Lichter-Konecki U, Konecki DS, Trefz FK, Dasovich M, Wang T, Henriksen K, Lou H, Woo SLC (1991) Molecular basis of phenotypic heterogeneity in PKU. N Engl J Med 324:1232–1238Google Scholar
  62. Orkin SH, Kazazian HH (1984) The mutation and polymorphism of the human β-globin gene and its surrounding DNA. Annu Rev Genet 18:131–171Google Scholar
  63. Özalp I, Coskun T, Ceyhan M, Tokol S, Oran O, Erdem G, Tekinalp G, Durmus Z, Tarikahya Y (1986) Incidence of phenylketonuria and hyperphenylalaninaemia in a sample of the Turkish newborn population. J Inher Metab Dis 9 [Suppl 2]:237–239Google Scholar
  64. Penrose LS (1935) Inheritance of phenylpyruvic amentia (phenylketonuria) Lancet II:192–194Google Scholar
  65. Rey F, Berthelon M, Caillaud C, Lyonnet S, Abadie V, BlandinSavoja F, Feingold J, Saudubray J, Frézal J, Munnich A, Rey J (1988) Clinical and molecular heterogeneity of phenylalanine hydroxylase deficiencies in France. Am J Hum Genet 43:914–921Google Scholar
  66. Riess O, Michel A, Speer A, Meiske W, Cobet G, Coutelle C (1988) 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 78:343–346Google Scholar
  67. Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N (1985) Enzymatic amplification of β-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230:1350–1354PubMedGoogle Scholar
  68. Saugstad LF (1976) Anthropological significance of phenylketonuria and the importance of heterozygote advantage. J Irish Med Assoc 69:405–410Google Scholar
  69. Scriver CR (1986) Soundings at the PKU locus. Trends Genet 2:251–252Google Scholar
  70. Scriver CR, Kaufman S, Woo SLC (1989) The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS (eds) The metabolic basis of inherited disease, vol 1. McGraw-Hill, pp 495–546Google Scholar
  71. Stuhrmann M, Reiss O, Mönch E, Kurdoglu G (1989) Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria. Clin Genet 36:117–121Google Scholar
  72. Sullivan SE, Lidsky AS, Brayton K, DiLella AG, King M, Connor F, Woo SLC (1985) Phenylalanine hydroxylase deletion mutant from a patient with classical PKU. Am J Hum Genet 37:A177Google Scholar
  73. Sullivan SE, Moore SD, Connor JM, King M, Cockburn F, Steinmann B, Gitzelmann R, Daiger SP, Woo SLC (1989) Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland. Am J Hum Genet 44:652–659Google Scholar
  74. Svensson E, Andersson B, Hagenfeldt L (1990) Two mutations with- in the coding sequence of the phenylalanine hydroxylase gene. Hum Genet 85:300–304Google Scholar
  75. Svensson E, Döbeln U von, Hagenfeldt L (1991) Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus and their relation to phenotype in Swedish phenylketonuria families. Hum Genet 87:11–17Google Scholar
  76. Thalhammer O (coordinator) (1975) Frequency of inborn errors of metabolism, especially PKU, in some representative newborn screening centers around the world. A collaborative study. Hum Genet 30:273–286Google Scholar
  77. Trefz FK, Schmidt H, Bartholomé K, Mahle M, Matthis P, Pecht G (1985) Differential diagnosis and significance of various hyperphenylalaninemias. In: Bickel H, Wachtel U (eds) Inherited diseases of amino acid metabolism. Thieme, Stuttgart New York, pp 86–100Google Scholar
  78. Trefz FK, Lichter-Konecki U, Konecki D (1989) Phenylketonuria. Curr Opinion Pediatr 1:421–427Google Scholar
  79. Trefz FK, Yoshino M, Nishiyori A, Aengeneyndt F, SchmidtMader B, Lichter-Konecki U, Konecki DS (1990) RFLP-patterns in Japanese PKU families: new polymorphisms for the mutant phenylalanine hydroxylase gene. Hum Genet 85:121–122Google Scholar
  80. Tsai TF, Hsiao KJ, Su TS (1990) Phenylketonuria mutation in Chinese haplotype 44 identical with haplotype 2 mutation in northern-European Caucasians. Hum Genet 84:409–411Google Scholar
  81. Veale AMO (1980) Screening for phenylketonuria. In: Bickel H, Guthrie R, Hammerson G (eds) Neonatal screening for inborn errors of metabolism. Springer, Berlin Heidelberg New York, pp 7–18Google Scholar
  82. Vogel F (1984) Clinical consequences of heterozygosity for autosomal-recessive diseases. Clin Genet 25:381–415Google Scholar
  83. Vosberg H-P (1989) The polymerase chain reaction: an improved method for the analysis of nucleic acids. Hum Genet 83:1–15Google Scholar
  84. Wang T, Okano Y, Eisensmith R, Huang S-Z, Zeng Y-T, Lo WHY, Woo SLC (1989a) Molecular genetics of phenylketonuria in Orientals: linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene. Am J Hum Genet 45:675–680Google Scholar
  85. Wang T, Okano Y, Eisensmith R, Zeng YT, Huang SZ, Lo WHY, Woo SLC (1989b) Molecular genetics of PKU in Orientals. Am J Hum Genet 45:A228Google Scholar
  86. Wang T, Okano Y, Eisensmith R, Fekete G, Schuler D, Berencsi G, Nasz I, Woo SLC (1990a) Molecular Genetics of PKU in eastern Europe: A nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene. Somat Cell Mol Genet 16:85–90Google Scholar
  87. Wang T, Okano Y, Eisensmith RC, Lo WHY, Zeng YT, Huang SZ, Woo SLC (1990b) Molecular basis and population genetics of PKU in the Orient. Am J Hum Genet 47:A241Google Scholar
  88. Woo SLC (1988) Collation of RFLP haplotypes at the phenylalanine hydroxylase (PAH) locus. Am J Hum Genet 43:781–783Google Scholar
  89. Woo SLC (1989) Molecular basis and population genetics of phenylketonuria. Biochemistry 28:1–7Google Scholar
  90. Woo SLC, Lidsky AS, Guttler F, Chandra T, Robson KJH (1983) Cloned human phenylalanine hydroxylase gene allows prenatal detection of classical phenylketonuria. Nature 306:151–155Google Scholar
  91. Woo SLC, Okano Y, Dasovich M, Wang, T, Güttler F, Lichter-Konecki U, Konecki DS, Swenson E, Hagenfeldt L, Rey F, Rey J, Cockburn F, Conner M, Gitzelmann R, Steinmenn B, Apold J, Eiken HG, Giovanini M, Riva E, Longhi R, Romano V, Cerone R, Naughten ER, Mullins C, Ölzap I, Fekete G, Schuler D, Berenssi G, Nasz I, Brdicka R, Kamaryt J, Pijackova A, Cabalska B, Boszkowa K, Schwartz E, Kalimin VN, Eisensmith R (1991) Molecular population dynamics of phenylketonuria among Caucasians: multiple founding populations in Europe. Am J Hum Genet (in press)Google Scholar
  92. Woolf LI (1976) A study of the cause of the high incidence of phenylketonuria in Ireland and West Scotland. J Irish Med Assoc 60:398–401Google Scholar
  93. Woolf LI (1986) The heterozygote advantage in phenylketonuria. Am J Hum Genet 38:773–775Google Scholar
  94. Zygulska M, Eigel A, Aulehla-Scholz C, Pietrzyk JJ, Horst J (1991) Molecular analysis of PKU haplotypes in the population of Southern Poland. Hum Genet (in press)Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • David S. Konecki
    • 1
  • Uta Lichter-Konecki
    • 1
  1. 1.Universitäts-KinderklinikHeidelbergGermany

Personalised recommendations