Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants(358 views) Daniele A, Cardillo G, Pennino C, Carbone MT, Scognamiglio D, Esposito L, Correra A, Castaldo G, Zagari A, Salvatore F
Keywords: Expression Studies Of Pku Mutants, Pku Mutations, Pku Mutations Functional Analysis, Structural Analysis, Phenylalanine 4 Monooxygenase, Article, Controlled Study, Crystal Structure, Enzyme Activity, Gene Mutation, Human, Human Cell, Hyperphenylalaninemia, Italy, Loading Test, Pathogenesis, Phenotype, Priority Journal, Protein Analysis, Protein Expression, Reverse Transcription Polymerase Chain Reaction, Western Blotting, Cell Line, Dna Mutational Analysis, Genetic Predisposition To Disease, Models, Molecular, Phenylalanine Hydroxylase, Phenylketonurias, Protein Structure, Secondary, Reverse Transcriptase Polymerase Chain Reaction,
Affiliations: *** IBB - CNR ***
CEINGE - Biotecnologie Avanzate Scarl, Via Comunale Margherita, 482, 80145 Naples, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Via S. Pansini, 5, 80131 Naples, Italy
Dipartimento di Scienze per la Salute, Università del Molise, Via F. De Sanctis, 86100 Campobasso, Italy
Centro Screening Fenilchetonuria, Ospedale SS. Annunziata, ASL Na1, Via Egiziaca a Forcella, 18, 80139 Naples, Italy
CNR - Istituto di Biostrutture e Bioimmagini, Via Mezzocannone, 16, 80134 Naples, Italy
SEMM - European School of Molecular Medicine, Naples Site - CEINGE, Italy
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C. R. Scriver, S. Kaufman, The hyperphenylalaninemias, in: C. R. Scriver, A. L. Beaudet, S. W. Sly, D. Valle (eds) B. Childs, K. W. Kinzler, B. Vogelstein (assoc. eds), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, 8 ed., Ch. 77Scriver, C. R., The PAH gene, phenylketonuria, and a paradigm shift (2007) Hum. Mutat., 28, pp. 831-84
Scriver, C. R., Waters, P. J., Monogenic traits are not simple. Lessons from phenylketonuria (1999) Trends Genet., 15, pp. 267-272
Hennermann, J. B., B hrer, C., Blau, N., Vetter, B., M nch, E., Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria (2005) Mol. Genet. Metab., 86, pp. S86-S90
Levy, H. L., Milanowski, A., Chakrapani, A., Cleary, M., Lee, P., Trefz, F. K., Whitley, C. B., Dorenbaum, A., Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study (2007) Lancet, 370, pp. 504-510
Burton, B. K., Grange, D. K., Milanowski, A., Vockley, G., Feillet, F., Crombez, E. A., Abadie, V., Dorenbaum, A., The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study (2007) Inherit. Metab. Dis., 30, pp. 700-707
Scriver, C. R., Hurtubise, M., Konecki, D., Phommarinh, M., Prevost, L., Erlandsen, H., Stevens, R., Sarkissian, C., PAHdb 2003: what a locus-specific knowledgebase can do? (2003) Hum. Mutat., 21, pp. 333-344
Waters, P. J., How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression (2003) Hum. Mutat., 21, pp. 357-369
Andersen, O. A., Flatmark, T., Hough, E., Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3- (2-thienyl) -l-alanine, and its implications for the mechanism of catalysis and substrate activation (2002) J. Mol. Biol., 320, pp. 1095-1108
Andersen, O. A., Stokka, A. J., Flatmark, T., Hough, E., 2. 0 resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3- (2-thienyl) -l-alanine or l-norleucine: substrate specificity and molecular motions related to substrate binding (2003) J. Mol. Biol., 333, pp. 747-757
Kim, S. W., Jung, J., Oh, H. J., Kim, J., Lee, K. S., Lee, D. H., Park, C., Jung, S. C., Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene (2006) Clin. Chim. Acta, 365, pp. 279-287
Mirisola, M. G., Cal, F., Gloria, A., Schinocca, P., D'Amato, M., Cassar, G., Leo, G. D., Romano, V., PAH gene mutations in the Sicilian population: association with minihaplotypes and expression analysis (2001) Mol. Genet. Metab., 74, pp. 353-361
Muntau, A. C., Roschinger, W., Habich, M., Demmelmair, H. H., Hoffmann, B., Sommhoff, C. P., Roscher, A. A., Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria (2002) N. Engl. J. Med., 347, pp. 2122-2132
Pey, A. L., Perez, B., Desviat, L. R., Martinez, M. A., Aguado, C., Erlandsen, H., Gamez, A., Martinez, A., Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations (2004) Hum. Mutat., 24, pp. 388-399
Stokka, A. J., Carvalho, R. N., Barroso, J. F., Flatmark, T., Probing the role of crystallographically defined/predicted hinge-bending regions in the substrate-induced global conformational transition and catalytic activation of human phenylalanine hydroxylase by single-site mutagenesis (2004) J. Biol. Chem., 279, pp. 26571-26580
Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants
Hyperphenylalaninemia is a group of autosomal recessive disorders caused by a wide range of phenylalanine hydroxylase (PAH) gene variants. To study the effects of mutations on PAH activity, we have reproduced five mutations (p.N223Y, p.R297L, p.F382L, p.K398N and p.Q419R) that we recently identified in a population of Southern Italy. Transient expression of mutant full-length cDNAs in human HEK293 cells yielded PAH variants whose L-phenylalanine hydroxylase activity was between 40% and 70% that of the wild-type enzyme. Moreover, Western blot analysis revealed a 50-kD monomer in all mutants thereby indicating normal synthesis of the mutant proteins. Because of the clinical mild nature of the phenotypes we performed an in vivo BH4 loading test. This was positive in all tested patients, which indicates that they are likely to respond to the coenzyme in vivo. We also analysed the environment of each mutation site in the available crystal structures of PAH by using molecular graphics tools. The structural alteration produced by each mutation was elucidated and correlated to the mutated properties of the mutant enzymes. All the data obtained demonstrate the disease-causing nature of the five novel variants. (C) 2008 Elsevier B.V. All rights reserved.
Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants
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Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants