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Connecting Mutant Phenylalanine Hydroxylase With Phenylketonuria

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Journal of Clinical Monitoring and Computing Aims and scope Submit manuscript

Abstract

Objective

The building of a quantitative relationship between genotype and phenotype would be great helpful for better clinical monitoring, diagnosis, prognosis and treatment. As the phenylketonuria is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase, in this study we build a descriptively quantitative relationship between mutant phenylalanine hydroxylase and classifications of phenylketonuria.

Methods

The amino-acid distribution probability is used to quantify the phenylalanine hydroxylase and its mutants, the cross-impact analysis is used to couple mutant phenylalanine hydroxylase and classifications of phenylketonuria, and the Bayesian equation is used to compute the probability that the phenylketonuria can be classified under mutations.

Results

The results show that the patient has more than 0.9 chance of being phenylketonuria when a new mutation occurs in phenylalanine hydroxylase.

Conclusions

The built relationship paves the way for modeling of this type relationship for better clinical monitoring, diagnosis, prognosis and treatment.

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References

  1. Chou KC Structure bioinformatics and its impact to biomedical science. Curr Med Chem 2004; 11: 2105–2134

    PubMed  CAS  Google Scholar 

  2. Wu G, Yan S Randomness in the primary structure of protein: methods and implications. Mol Biol Today 2002; 3: 55–69

    CAS  Google Scholar 

  3. Wu G, Yan S Mutation trend of hemagglutinin of influenza A virus: a review from computational mutation viewpoint. Acta Pharmacol Sin 2006; 27: 513–526

    Article  PubMed  CAS  Google Scholar 

  4. Wu G, Yan S Lecture notes on computational mutation. Nova Science Publishers, New York, 2008

    Google Scholar 

  5. Santos LL, Magalhães MC, Januário JN, Aguiar MJB, Carvalho MRS The time has come: a new scene for PKU. Genet Mol Res 2006; 5: 33–44

    PubMed  Google Scholar 

  6. Acosta A, Silva W Jr, Carvalho T, Gomes M, Zago MA Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria. Hum Mutat 2001; 17: 122–130

    Article  PubMed  CAS  Google Scholar 

  7. Christ SE Abjorn Folling and the discovery of phenylketonuria. J Hist Neurosci 2003; 12: 44–54

    Article  PubMed  Google Scholar 

  8. Perez-Duenas B, Vilaseca MA, Mas A, Lambruschini N, Artuch R, Gómez L, Pineda J, Gutiérrez A, Mila M, Campistol J Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clin Biochem 2004; 37: 1083–1090

    Article  PubMed  CAS  Google Scholar 

  9. National Newborn Screening and Genetics Resource Center. National newborn screening report: 2000. National Newborn Screening and Genetics Resource Center, Austin, Tex, 2003

  10. Gjetting T, Petersen M, Guldberg P, Guettler F Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Am J Hum Genet 2001; 68: 1353–1360

    Article  PubMed  CAS  Google Scholar 

  11. Centerwall SA, Centerwall WR The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist. Pediatrics 2000; 105: 89–103

    Article  PubMed  CAS  Google Scholar 

  12. Caldwell J Pharmacogenetics and individual variation in the range of amino acid adequacy: the biological aspects. J Nutr 2004; 134: 1600S–1604S

    PubMed  CAS  Google Scholar 

  13. Waters PJ, Parniak MA, Hewson AS, Scriver CR Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene. Hum Mutat 1998; 12: 344–354

    Article  PubMed  CAS  Google Scholar 

  14. Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N, Sakamoto O, Fugii K, Matsubara Y, Narisawa K Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 1999; 135: 375–378

    Article  PubMed  CAS  Google Scholar 

  15. Gjetting T, Romstad A, Haavik J, Knappskog PM, Acosta AX, Silva WA Jr, Zago MA, Guldberg P, Güttler F A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics. Mol Genet Metab 2001; 73: 280–284

    Article  PubMed  CAS  Google Scholar 

  16. OMIM – Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM, 2000

  17. Scriver CR, Kaufman S Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. in: CR Scriver, AL Beaudet, WS Sly, B Childs, KW Kinzler, B Vogelstein (Eds.), The metabolic, molecular bases of inherited disease, 8th ed., McGraw-Hill Inc., New York, 2001, pp. 1667–1724

    Google Scholar 

  18. Pitt D The natural history of untreated phenylketonuria. Med J Aust 1971; 1: 378–383

    PubMed  CAS  Google Scholar 

  19. Dipple KM, McCabe ER Phenotypes of patients with “simple” Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000; 66: 1729–1735

    Article  PubMed  CAS  Google Scholar 

  20. Scriver CR Why mutation analysis does not always predict clinical consequences: explanations in the era of genomics. J Pediatr 2002; 140: 502–506

    PubMed  Google Scholar 

  21. Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev 2007; 17: 91–101

    Article  PubMed  CAS  Google Scholar 

  22. Benit P, Rey F, Melle D, Munnich A, Rey J Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria. Hum Mutat 1994; 4: 229–231

    Article  PubMed  CAS  Google Scholar 

  23. Guldberg P, Mallmann R, Henriksen KF, Guettler F Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations. Hum Mutat 1996; 8: 276–279

    Article  PubMed  CAS  Google Scholar 

  24. Michiels L, Francois B, Raus J, Vandevyver C Identification of seven new mutations in the phenylalanine hydroxylase gene, associated with hyperphenylalaninemia in the Belgian population. Hum Mutat Suppl 1998; 1: S123–S124

    Google Scholar 

  25. Scriver CR, Hurtubise M, Konecki D, Phommarinh M, Prevost L, Erlandsen H, Stevens R, Waters PJ, Ryan S, McDonald D, Sarkassian C PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat 2003; 21: 333–344

    Article  PubMed  CAS  Google Scholar 

  26. Pey AL, Desviat LR, Gamez A, Ugarte M, Perez B Phenylketonuria: genotype–phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 2003; 21: 370–378

    Article  PubMed  CAS  Google Scholar 

  27. Gao N, Yan S, Wu G Pattern of positions sensitive to mutations in human haemoglobin α-chain. Protein Pept Lett 2006; 13: 101–107

    Article  PubMed  CAS  Google Scholar 

  28. Wu G, Yan S Prediction of distributions of amino acids and amino acid pairs in human haemoglobin α-chain and its seven variants causing α-thalassemia from their occurrences according to the random mechanism. Comp Haematol Int 2000; 10: 80–84

    Article  CAS  Google Scholar 

  29. Wu G, Yan S Analysis of distributions of amino acids, amino acid pairs and triplets in human insulin precursor and four variants from their occurrences according to the random mechanism. J Biochem Mol Biol Biophys 2001; 5: 293–300

    CAS  Google Scholar 

  30. Wu G, Yan S Analysis of distributions of amino acids and amino acid pairs in human tumor necrosis factor precursor and its eight variants according to random mechanism. J Mol Model 2001; 7: 318–323

    CAS  Google Scholar 

  31. Wu G, Yan S Random analysis of presence and absence of two- and three-amino-acid sequences and distributions of amino acids, two- and three-amino-acid sequences in bovine p53 protein. Mol Biol Today 2002; 3: 31–37

    CAS  Google Scholar 

  32. Wu G, Yan S Analysis of distributions of amino acids in the primary structure of apoptosis regulator Bcl-2 family according to the random mechanism. J Biochem Mol Biol Biophys 2002; 6: 407–414

    Article  PubMed  CAS  Google Scholar 

  33. Wu G, Yan S Analysis of distributions of amino acids in the primary structure of tumor suppressor p53 family according to the random mechanism. J Mol Model 2002; 8: 191–198

    Article  PubMed  CAS  Google Scholar 

  34. Wu G, Yan S Determination of sensitive positions to mutations in human p53 protein. Biochem Biophys Res Commun 2004; 321: 313–319

    Article  PubMed  CAS  Google Scholar 

  35. Wu G, Yan S Searching of main cause leading to severe influenza A virus mutations and consequently to influenza pandemics/epidemics. Am J Infect Dis 2005; 1: 116–123

    Article  CAS  Google Scholar 

  36. Wu G, Yan S Prediction of mutation trend in hemagglutinins and neuraminidases from influenza A viruses by means of cross-impact analysis. Biochem Biophys Res Commun 2005; 326: 475–482

    Article  PubMed  CAS  Google Scholar 

  37. Wu G, Yan S Timing of mutation in hemagglutinins from influenza A virus by means of amino-acid distribution rank and fast Fourier transform. Protein Pept Lett 2006; 13: 143–148

    Article  PubMed  CAS  Google Scholar 

  38. Wu G, Yan S Prediction of possible mutations in H5N1 hemagglutinins of influenza A virus by means of logistic regression. Comp Clin Pathol 2006; 15: 255–261

    Article  CAS  Google Scholar 

  39. Wu G, Yan S Prediction of mutations in H5N1 hemagglutinins from influenza A virus. Protein Pept Lett 2006; 13: 971–976

    Article  PubMed  CAS  Google Scholar 

  40. Wu G, Yan S Improvement of model for prediction of hemagglutinin mutations in H5N1 influenza viruses with distinguishing of arginine, leucine and serine. Protein Pept Lett 2007; 14: 191–196

    Article  PubMed  CAS  Google Scholar 

  41. Wu G, Yan S Improvement of prediction of mutation positions in H5N1 hemagglutinins of influenza A virus using neural network with distinguishing of arginine, leucine and serine. Protein Pept Lett 2007; 14: 465–470

    Article  PubMed  Google Scholar 

  42. Wu G, Yan S Prediction of mutations engineered by randomness in H5N1 neuraminidases from influenza A virus. Amino Acids 2007; 34: 81–90

    Article  PubMed  CAS  Google Scholar 

  43. Wu G, Yan S Prediction of mutations in H1 neuraminidases from North America influenza A virus engineered by internal randomness. Mol Divers 2007; 11: 131–140

    Article  PubMed  CAS  Google Scholar 

  44. Wu G, Yan S Prediction of mutations initiated by internal power in H3N2 hemagglutinins of influenza A virus from North America. Int J Pept Res Ther 2008; 14: 41–51

    Article  CAS  Google Scholar 

  45. Wu G, Yan S Prediction of mutation in H3N2 hemagglutinins of influenza A virus from North America based on different datasets. Protein Pept Lett 2008; 15: 144–152

    PubMed  CAS  Google Scholar 

  46. Wu G, Yan S Building quantitative relationship between changed sequence and changed oxygen affinity in human hemoglobin β-chain. Protein Pept Lett 2008; 15: 341–345

    Article  PubMed  CAS  Google Scholar 

  47. Feller W An introduction to probability theory, its applications. 3rd ed, Vol I. Wiley, New York, 1968, pp. 34–40

    Google Scholar 

  48. Abramowitz M, Stequn IA Handbook of mathematical functions with formulas, graphs, mathematical tables. Dover Publications, New York, 1965, p. 831

    Google Scholar 

  49. Hennermann JB, Vetter B, Wolf C, Windt E, Bührdel P, Seidel J, Mönch E, Kulozik AE Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. Hum Mutat 2000; 15: 254–260

    Article  PubMed  CAS  Google Scholar 

  50. Yang Y, Drummond-Borg M, Garcia-Heras J Molecular analysis of phenylketonuria (PKU) in newborns from Texas. Hum Mutat 2001; 17: 523

    Article  PubMed  CAS  Google Scholar 

  51. Waters PJ, Parniak MA, Nowacki P, Scriver CR In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function, Hum Mutat 1998; 11: 4–17

    Article  PubMed  CAS  Google Scholar 

  52. Gordon TG Cross-impact matrices – an illustration of their use for policy analysis. Futures 1969; 2: 527–531

    Article  Google Scholar 

  53. Gordon TG, Hayward H Initial experiments with the cross-impact matrix method of forecasting. Futures 1968; 1: 100–116

    Article  Google Scholar 

  54. Enzer S Delphi and cross-impact techniques: an effective combination for systematic futures analysis. Futures 1970; 3: 48–61

    Google Scholar 

  55. Enzer S Cross-impact techniques in technology assessment. Futures 1970; 4: 30–51

    Article  Google Scholar 

  56. Sage AP Methodology for large-scale systems. McGraw-Hill, New York, 1977, pp. 165–203

    Google Scholar 

  57. Wu G Application of cross-impact analysis to the relationship between aldehyde dehydrogenase 2 and flushing. Alcohol Alcohol 2000; 35: 55–59

    PubMed  CAS  Google Scholar 

  58. Wikipedia – the free encyclopedia, Bayes’ theorem. http://en.wikipedia.org/wiki/Bayes’_theorem, 2007

  59. PAH Mutation Analysis Consortium. http://www.pahdb.mcgill.ca/, 2003

  60. Clark AG Mutation-selection balance with multiple alleles. Genetica 1998; 102–103: 41–47

    Article  PubMed  Google Scholar 

  61. Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F 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; 63: 71–79

    Article  PubMed  CAS  Google Scholar 

  62. Rivera I, Cabral A, Almeida M, Leandro P, Carmona C, Eusébio F, Tasso T, Vilarinho L, Martins E, Lechner MC, de Almeida IT, Konecki DS, Lichter-Konecki U The correlation of genotype and phenotype in Portuguese hyperphenylalaninemic patients. Mol Genet Metab 2000; 69: 195–203

    Article  PubMed  CAS  Google Scholar 

  63. Kasnauskiene J, Cimbalistiene L, Kucinskas V Validation of PAH genotype-based predictions of metabolic phenylalanine hydroxylase deficiency phenotype: investigation of PKU/MHP patients from Lithuania. Med Sci Monit 2003; 9: CR142–CR146

    PubMed  Google Scholar 

  64. Smith I, Wolff OH Natural history of phenylketonuria and influence of early treatment, Lancet 1974; 2: 540–544

    Article  PubMed  CAS  Google Scholar 

  65. Berry HK, O’Grady DJ, Perlmutter LJ, Bofinger MK Intellectual development and academic achievement of children treated early for phenylketonuria. Dev Med Child Neurol 1979; 21: 311–320

    Article  PubMed  CAS  Google Scholar 

  66. Pietz J, Benninger C, Schmidt H, Scheffner D, Bickel H Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early. Eur J Pediatr 1988; 147: 361–367

    Article  PubMed  CAS  Google Scholar 

  67. Brosco JP, Mattingly MM, Sanders LM Impact of specific medical interventions on reducing the prevalence of mental retardation. Arch Pediatr Adolesc Med 2006; 160: 302–309

    Article  PubMed  Google Scholar 

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Acknowledgment

This study is supported in part by National Natural Science Foundation No. 20666002 (Guangxi Assignment No. 0728001).

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Authors and Affiliations

  1. Guangxi Academy of Sciences, 98 Daling Road, Nanning, Guangxi, 530007, China

    Shaomin Yan MD PhD

  2. Computational Mutation Project, DreamSciTech Consulting, 301, Building 12, Nanyou A-zone, Jiannan Road, Shenzhen, Guangdong, 518054, China

    Guang Wu MD PhD

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  1. Shaomin Yan MD PhD
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  2. Guang Wu MD PhD
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Correspondence to Guang Wu MD PhD.

Additional information

Yan S, Wu G. Connecting mutant phenylalanine hydroxylase with phenylketonuria.

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Yan, S., Wu, G. Connecting Mutant Phenylalanine Hydroxylase With Phenylketonuria. J Clin Monit Comput 22, 333–342 (2008). https://doi.org/10.1007/s10877-008-9139-7

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  • DOI: https://doi.org/10.1007/s10877-008-9139-7

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