Co-expression of phenylalanine hydroxylase variants and effects of interallelic complementation on in vitro enzyme activity and genotype-phenotype correlation

Molecular Genetics and Metabolism

Volumn 117, Issue 3, 2016, Pages 328-335

  Shen, Nan ^a   Heintz, Caroline ^b   Thiel, Christian ^a   Okun, Jürgen G ^a   Hoffmann, Georg F ^a   Blau, Nenad ^a  

^a UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^b HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Hyperphenylalaninemia; Phenylketonuria; PKU; Tetrahydrobiopterin

Indexed keywords

ENZYME VARIANT; PHENYLALANINE 4 MONOOXYGENASE; TETRAHYDROBIOPTERIN; BIOPTERIN; HYBRID PROTEIN; SAPROPTERIN;

ALLELE; AMINO TERMINAL SEQUENCE; ARTICLE; CONTROLLED STUDY; COS 7 CELL LINE; ELECTROSPRAY MASS SPECTROMETRY; ENZYME ACTIVITY; EXPRESSION VECTOR; GENETIC COMPLEMENTATION; GENOTYPE; GENOTYPE PHENOTYPE CORRELATION; HUMAN; HYPERPHENYLALANINEMIA; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; NONHUMAN; PHENOTYPE; PHENYLKETONURIA; PRIORITY JOURNAL; PROTEIN EXPRESSION; TANDEM MASS SPECTROMETRY; WESTERN BLOTTING; WILD TYPE; ANALOGS AND DERIVATIVES; ANIMAL; CHLOROCEBUS AETHIOPS; COS CELL LINE; FEMALE; GENE VECTOR; GENETIC ASSOCIATION STUDY; GENETICS; HETEROZYGOTE; METABOLISM; MUTATION;

ALLELES; ANIMALS; BIOPTERIN; CERCOPITHECUS AETHIOPS; CHROMATOGRAPHY, LIQUID; COS CELLS; FEMALE; GENETIC ASSOCIATION STUDIES; GENETIC COMPLEMENTATION TEST; GENETIC VECTORS; GENOTYPE; HETEROZYGOTE; HUMANS; MUTATION; PHENOTYPE; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIAS; RECOMBINANT FUSION PROTEINS; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION;

EID: 84959451097     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2016.01.004     Document Type: Article

References (40)

1. Blau N., Van Spronsen F.J., Levy H.L. Phenylketonuria. Lancet 2010, 376:1417-1427.
2. Blau N., Shen N., Carducci C. Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert. Rev. Mol. Diagn. 2014, 14:655-671.
3. Zschocke J. Phenylketonuria mutations in Europe. Hum. Mutat. 2003, 21:345-356.
4. Guldberg P., Romano V., Ceratto N., Bosco P., Ciuna M., Indelicato A., Mollica F., Meli C., Giovannini M., Riva E., et al. Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. Hum. Mol. Genet. 1993, 2:1703-1707.
5. Scriver C.R. The PAH gene, phenylketonuria, and a paradigm shift. Hum. Mutat. 2007, 28:831-845.
6. Dipple K.M., McCabe E.R. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am. J. Hum. Genet. 2000, 66:1729-1735.
7. Wettstein S., Underhaug J., Perez B., Marsden B.D., Yue W.W., Martinez A., Blau N. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria. Eur. J. Hum. Genet. 2015, 23:302-309.
8. Dobrowolski S.F., Heintz C., Miller T., Ellingson C.R., Ellingson C.C., Özer I., Gökcay 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, 10:116-121.
9. Kure S., Hou D.C., Ohura T., Iwamoto H., Suzuki S., Sugiyama N., Sakamoto O., Fujii K., Matsubara Y., Narisawa K. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J. Pediatr. 1999, 135:375-378.
10. Blau N., Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol. Genet. Metab. 2004, 82:101-111.
11. Zurflüh M.R., Zschocke J., Lindner M., Feillet F., Chery C., Burlina A., Stevens R., Thöny B., Blau N. Molecular genetics of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency. Hum. Mutat. 2008, 29:167-175.
12. Levy H., Milanowski A., Chakrapani A., Cleary M., Lee P., Trefz F.K., Whitley C.B., Feillet F., Feigenbaum A.S., Bebchuk J.D., Christ-Schmidt H., Dorenbaum A. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomized placebo-controlled study. Lancet 2007, 370:504-510.
13. Siddiqi O. Interallelic complementation in vivo and in vitro. Br. Med. Bull. 1965, 21:249-253.
14. Leandro J., Nascimento C., de Almeida I.T., Leandro P. Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim. Biophys. Acta 2006, 1762:544-550.
15. Leandro J., Leandro P., Flatmark T. Heterotetrameric forms of human phenylalanine hydroxylase: co-expression of wild-type and mutant forms in a bicistronic system. Biochim. Biophys. Acta 2011, 1812:602-612.
16. Danecka M.K., Woidy M., Zschocke J., Feillet F., Muntau A.C., Gersting S.W. Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. J. Med. Genet. 2015, 52:175-185.
17. Heintz C., Cotton R.G., Blau N. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase and importance of genotypes for pharmacological therapy of phenylketonuria. Hum. Mutat. 2013, 34:927-936.
18. Heintz C., Troxler H., Martinez A., Thony B., Blau N. Quantification of phenylalanine hydroxylase activity by isotope-dilution liquid chromatography-electrospray ionization tandem mass spectrometry. Mol. Genet. Metab. 2012, 105:559-565.
19. Veitia R.A. Dominant negative factors in health and disease. J. Pathol. 2009, 218:409-418.
20. Dobrowolski S.F., Pey A.L., Koch R., Levy H., Ellingson C.C., Naylor E.W., Martinez A. Biochemical characterization of mutant phenylalanine hydroxylase enzymes and correlation with clinical presentation in hyperphenylalaninaemic patients. J. Inherit. Metab. Dis. 2009, 32:10-21.
21. Trefz F.K., Scheible D., Gotz H., Frauendienst-Egger G. Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. J. Inherit. Metab. Dis. 2009, 32:22-26.
22. Vela-Amieva M., Abreu-Gonzalez M., Gonzalez-Del A.A., Ibarra-Gonzalez I., Fernandez-Lainez C., Barrientos-Rios R., Monroy-Santoyo S., Guillen-Lopez S., Alcantara-Ortigoza M.A. Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect. Clin. Genet. 2015, 88:62-67.
23. Trunzo R., Santacroce R., D'Andrea G., Longo V., De Girolamo G., Dimatteo C., Leccese A., Bafunno V., Lillo V., Papadia F., Margaglione M. Phenylalanine hydroxylase deficiency in South Italy: genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH responsiveness. Clin. Chim. Acta 2015, 450:51-55.
24. Zhu T., Ye J., Han L., Qiu W., Zhang H., Liang L., Gu X. Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. Gene 2013, 529:80-87.
25. Polak E., Ficek A., Radvanszky J., Soltysova A., Urge O., Cmelova E., Kantarska D., Kadasi L. Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. Gene 2013, 526:347-355.
26. Santos L.L., Fonseca C.G., Starling A.L., Januario J.N., Aguiar M.J., Peixoto M.G., Carvalho M.R. Variations in genotype-phenotype correlations in phenylketonuria patients. Genet. Mol. Res. 2010, 9:1-8.
27. Daniele A., Scala I., Cardillo G., Pennino C., Ungaro C., Sibilio M., Parenti G., Esposito L., Zagari A., Andria G., Salvatore F. Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy. FEBS J. 2009, 276:2048-2059.
28. Rivera I., Mendes D., Afonso A., Barroso M., Ramos R., Janeiro P., Oliveira A., Gaspar A., I T.d.A. Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. Mol. Genet. Metab. 2011, 104:S86-S92. Suppl.
29. Blau N., Hennermann J.B., Langenbeck U., Lichter-Konecki U. Diagnosis, classification and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol. Genet. Metab. 2011, 104:S2-S9.
30. Waters P.J., Parniak M.A., Nowacki P., Scriver C.R. In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. Hum. Mutat. 1998, 11:4-17.
31. Gjetting T., Petersen M., Guldberg P., Guttler 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, 72:132-143.
32. Erlandsen H., Stevens R.C. The structural basis of phenylketonuria. Mol. Genet. Metab. 1999, 68:103-125.
33. Pey A.L., Desviat L.R., 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.
34. Erlandsen H., Pey A.L., Gamez A., Perez B., Desviat L.R., Aguado C., Koch R., Surendran S., Tyring S., Matalon R., Scriver C.R., Ugarte M., Martinez A., Stevens R.C. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc. Natl. Acad. Sci. U. S. A. 2004, 101:16903-16908.
35. Shi Z., Sellers J., Moult J. Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. Proteins 2012, 80:61-70.
36. Carluccio C., Fraternali F., Salvatore F., Fornili A., Zagari A. Structural features of the regulatory ACT domain of phenylalanine hydroxylase. PLoS One 2013, 8.
37. Underhaug J., Aubi O., Martinez A. Phenylalanine hydroxylase misfolding and pharmacological chaperones. Curr. Top. Med. Chem. 2013, 12:2534-2545.
38. Gersting S.W., Kemter K.F., Staudigl M., Messing D.D., Danecka M.K., Lagler F.B., Sommerhoff C.P., Roscher A.A., Muntau A.C. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am. J. Hum. Genet. 2008, 83:5-17.
39. Pey A.L., Martinez A. The activity of wild-type and mutant phenylalanine hydroxylase and its regulation by phenylalanine and tetrahydrobiopterin at physiological and pathological concentrations: an isothermal titration calorimetry study. Mol. Genet. Metab. 2005, 86:43-53.
40. Staudigl M., Gersting S.W., Danecka M.K., Messing D.D., Woidy M., Pinkas D., Kemter K.F., Blau N., Muntau A.C. The interplay between genotype, metabolic state, and cofactor treatment governs phenylalanine hydroxylase function and drug response. Hum. Mol. Genet. 2011, 20:2628-2641.