Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria

Journal of Medical Genetics

Volumn 52, Issue 3, 2015, Pages 175-185

  Danecka, Marta K ^a   Woidy, Mathias ^a   Zschocke, Johannes ^b   Feillet, François ^c   Muntau, Ania C ^d   Gersting, Søren W ^a  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^c CHU NANCY BRABOIS   (France)

^d UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

PHENYLALANINE; PHENYLALANINE 4 MONOOXYGENASE; TETRAHYDROBIOPTERIN;

ARTICLE; ENZYME ACTIVITY; EUROPE; GENE FREQUENCY; GENE FUNCTION; GENE MAPPING; GENOTYPE; HETEROZYGOTE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HOMOZYGOTE; HUMAN; MIDDLE EAST; MISSENSE MUTATION; PERSONALIZED MEDICINE; PHENOTYPE; PHENYLKETONURIA; PRIORITY JOURNAL; PROTEIN HOMEOSTASIS; GENETIC ASSOCIATION STUDY; GENETICS; MUTATION; PATHOPHYSIOLOGY;

EUROPE; GENETIC ASSOCIATION STUDIES; GENOTYPE; HUMANS; MIDDLE EAST; MUTATION; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIAS; PRECISION MEDICINE;

EID: 84930658078     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmedgenet-2014-102621     Document Type: Article

References (42)

1. Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat 2007;28:831-45.
2. Donlon J, Levy HL, Scriver CR. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson KM, Mitchell G. eds. The online metabolic & molecular bases of inherited disease. McGraw-Hill, 2008:1-150.
3. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet 2010;376:1417-27.
4. Zschocke J. Phenylketonuria mutations in Europe. Hum Mutat 2003;21:345-56.
5. Gjetting T, Petersen M, Guldberg P, Güttler F. In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. Mol Genet Metab 2001;72:132-43.
6. Pey AL, Stricher F, Serrano L, Martinez A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am J Hum Genet 2007;81:1006-24.
7. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A, Sapropterin Research G. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007;370:504-10.
8. Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 2002;347:2122-32.
9. Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, Ozer I, Gokcay G, Baykal T, Thöny B, Demirkol M, Blau N. Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Mol Genet Metab 2011;102:116-21.
10. Karaičić I, Meili D, Sarnavka V, Heintz C, Thöny B, Ramadža DP, Fumić K, Mardešić D, Barić I, Blau N. Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab 2009;97:165-71.
11. Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Belanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, Muntau AC, Bosch AM, Meli CA, Billette de Villemeur T, Kern I, Riva E, Giovannini M, Damaj L, Leuzzi V, Blau N. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics 2013;131:e1881-8.
12. Erlandsen H, Pey AL, Gamez A, Perez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martinez A, Stevens RC. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci USA 2004;101:16903-8.
13. Gersting SW, Kemter KF, Staudigl M, Messing DD, Danecka MK, Lagler FB, Sommerhoff CP, Roscher AA, Muntau AC. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet 2008;83:5-17.
14. Gersting SW, Lagler FB, Eichinger A, Kemter KF, Danecka MK, Messing DD, Staudigl M, Domdey KA, Zsifkovits C, Fingerhut R, Glossmann H, Roscher AA, Muntau AC. Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Hum Mol Genet 2010;19:2039-49.
15. Muntau AC, Gersting SW. Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism. J Inherit Metab Dis 2010;33:649-58.
16. Pey AL, Desviat LR, Gamez A, Ugarte M, Pérez B. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 2003;21:370-8.
17. Waters PJ, Parniak MA, Akerman BR, Scriver CR. Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype. Mol Genet Metab 2000;69:101-10.
18. Gámez A, Pérez B, Ugarte M, Desviat LR. Expression analysis of phenylketonuria mutations. Effect on folding and stability of the phenylalanine hydroxylase protein. J Biol Chem 2000;275:29737-42.
19. Stojiljkovic M, Perez B, Desviat LR, Aguado C, Ugarte M, Pavlovic S. The Missense p.S231F phenylalanine hydroxylase gene mutation causes complete loss of enzymatic activity in vitro. Protein J 2009;28:294-9.
20. Staudigl M, Gersting SW, Danecka MK, Messing DD, Woidy M, Pinkas D, Kemter KF, Blau N, Muntau AC. The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. Hum Mol Genet 2011;20:2628-41.
21. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 2014;16:188-200.
22. Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Dorenbaum A, Bebchuk J, Christ-Schmidt H, Seashore M, Giovannini M, Burton BK, Morris AA, Sapropterin Research G. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 2008;146A:2851-9.
23. Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB, Sapropterin Study G. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 2009;154:700-7.
24. Aguado C, Pérez B, Ugarte M, Desviat LR. Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells. FEBS Lett 2006;580:1697-701.
25. Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 2004;82:101-11.
26. Kaufman S, Max EE, Kang ES. Phenylalanine hydroxylase activity in liver biopsies from hyperphenylalaninemia heterozygotes: deviation from proportionality with gene dosage. Pediatr Res 1975;9:632-4.
27. Leandro J, Nascimento C, de Almeida IT, Leandro P. Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim Biophys Acta 2006;1762:544-50.
28. Zschocke J. Dominant versus recessive: molecular mechanisms in metabolic disease. J Inherit Metab Dis 2008;31:599-618.
29. Bélanger-Quintana A, Burlina A, Harding CO, Muntau AC. Up to date knowledge on different treatment strategies for phenylketonuria. Mol Genet Metab 2011;104 (Suppl):S19-25.
30. Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 2011;104(Suppl):S2-9.
31. Muntau AC, Leandro J, Staudigl M, Mayer F, Gersting SW. Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators. J Inherit Metab Dis 2014 37:505-23.
32. Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Guttler 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;63:71-9.
33. Cleary M, Trefz F, Muntau AC, Feillet F, van Spronsen FJ, Burlina A, Bélanger-Quintana A, Gizewska M, Gasteyger C, Bettiol E, Blau N, MacDonald A. Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes. Mol Genet Metab 2013;110:418-23.
34. Heintz C, Cotton RG, Blau N. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 2013;34:927-36.
35. Ribas GS, Sitta A, Wajner M, Vargas CR. Oxidative stress in phenylketonuria: what is the evidence? Cell Mol Neurobiol 2011;31:653-62.
36. Leuders S, Wolfgart E, Ott T, du Moulin M, van Teeffelen-Heithoff A, Vogelpohl L, Och U, Marquardt T, Weglage J, Feldmann R, Rutsch F. Influence of PAH genotype on sapropterin response in PKU: results of a single-center cohort study. JIMD Rep 2014;13:101-9.
37. Leuzzi V, Carducci C, Carducci C, Chiarotti F, Artiola C, Giovanniello T, Antonozzi I. The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. J Inherit Metab Dis 2006;29:38-46.
38. Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 2008;29:167-75.
39. Dipple KM, McCabe ER. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000;66:1729-35.
40. Enns GM, Martinez DR, Kuzmin AI, Koch R, Wakeem CK, Woo SL, Eisensmith RC, Packman S. Molecular correlations in phenylketonuria: mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population. Pediatr Res 1999;46:594-602.
41. Scriver CR, Waters PJ. Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 1999;15:267-72.
42. Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria. Eur J Hum Genet 2014. DOI: 10.1038/ejhg.2014.114