Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy (360 views)
Febs Journal (ISSN: 1742-464x), 2009 Apr; 276(7): 2048-2059.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 3.042, 5-year impact factor: 3.276
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-62149087350&partnerID=40&md5=7130d08828fde13c4335db8d52b99d56
Keywords: Bh4-Responsiveness, Hyperphenylalaninemia, Molecular Epidemiology, Pah Mutation Functional Analysis, Pah Structural Alterations, Phenylketonuria, Phenylalanine 4 Monooxygenase, Adolescent, Adult, Article, Child, Controlled Study, Enzyme Active Site, Enzyme Activity, Exon, Female, Gene Mutation, Genotype Phenotype Correlation, Human, In Vivo Study, Italy, Major Clinical Study, Preschool Child, Priority Journal, Protein Stability, Amino Acid Sequence, Dihydropteridine Reductase, Models, Molecular Sequence Data, Phenylalanine Hydroxylase, Protein Conformation,
Affiliations:
*** IBB - CNR ***
CEINGE-Biotecnologie Avanzate Scarl, Naples, Italy
IRCCS - Fondazione SDN, Naples, Italy
Dipartimento di Scienze per la Salute, Università Del Molise, Campobasso, Italy
Dipartimento di Pediatria, Università di Napoli 'Federico II', Naples, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli 'Federico II', Naples, Italy
CNR - Istituto di Biostrutture e Bioimmagini, Naples, Italy
CEINGE Biotecnologie, Avanzate S.C.a R.l., via Comunale Margherita 482, I-80145 Napoli, Italy
References:
Scriver, C.R., Kaufman, S., Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th Edn (, pp. 1667-1724. , In: Scriver, C.R., Kaufman, S., Eisensmith, R.C. Woo, S.L.C., eds), pp. McGraw-Hill, New York, N
Scriver, C.R., The PAH gene, phenylketonuria, and a paradigm shift (2007) Hum Mutat, 28, pp. 831-845
Giovannini, M., Verduci, M.E., Salvatici, E., Fiori, L., Riva, E., Phenylketonuria: Dietary and therapeutic challenges (2007) J Inherit Metab Dis, 30, pp. 145-152
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 (2006) J Inherit Metab Dis, 29, pp. 38-46
Levy, H.L., Milanowski, A., Chakrapani, A., Cleary, M., Lee, P., Trefz, F.K., Whitley, C.B., Bebchuk, J.D., 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., Dobbelaere, D., 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
Giannattasio, S., Dianzani, I., Lattanzi, P., Spada, M., Romano, V., Calì, F., Andria, G., Piazza, A., Genetic heterogeneity in five Italian regions: Analysis of PAH mutations and minihaplotypes (2001) Hum Hered, 52, pp. 154-159
Zschocke, J., Phenylketonuria mutations in Europe (2003) Hum Mutat, 21, pp. 345-356
Daniele, A., Cardillo, G., Pennino, C., Carbone, M.T., Scognamiglio, D., Correra, A., Pignero, A., Salvatore, F., Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: A 96% detection rate with ten novel mutations (2007) Ann Hum Genet, 71, pp. 185-193
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
Kayaalp, E., Treacy, E., Waters, P.J., Byck, S., Nowacki, P., Scriver, C.R., Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: A metanalysis of genotype-phenotype correlations (1997) Am J Hum Genet, 61, pp. 1309-1317
Scriver, C.R., Waters, P.J., Monogenic traits are not simple. Lessons from phenylketonuria (1999) Trends Genet, 15, pp. 267-272
Okano, Y., Eisensmith, R.C., Güttler, F., Lichter-Konecki, U., Konecki, D.S., Trefz, F.K., Dasovich, M., Lou, H., Molecular basis of phenotypic heterogeneity in phenylketonuria (1991) N Engl J Med, 324, pp. 1232-1238
Scriver, C.R., Phenylketonuria-genotypes and phenotype (1991) N Engl J Med, 324, pp. 1280-1281
Svensson, E., Von Döbeln, U., Eisensmit, R.C., Hagenfeldt, L., Woo, S.L., Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients (1993) Eur J Pediatr, 152, pp. 132-139
Trefz, F.K., Burgard, P., König, T., Goebel-Schreiner, B., Lichter-Konecki, U., Konecki, D., Schmidt, E., Bickel, H., Genotype-phenotype correlations in phenylketonuria (1993) Clin Chim Acta, 217, pp. 15-21
Fincham, J.R.S., Pateman, J.A., Formation of an enzyme through complementary action of mutant 'alleles' in separate nuclei in a heterocaryon (1957) Nature, 179, pp. 741-742
Ponzone, A., Spada, M., Roasio, L., Porta, F., Mussa, A., Ferraris, S., Impact of neonatal protein metabolism and nutrition on screening for phenylketonuria (2008) J Pediatr Gastroenterol Nutr, 46, pp. 561-569
Spaapen, L.J.M., Rubio-Gozalbo, M.E., Tetrahydrobiopterine-responsive phenylalanine hydroxylase deficiency, state of the art (2003) Mol Genet Metab, 78, pp. 93-99
Zurflüh, M.R., Zschocke, J., Lindner, M., Feillet, F., Chery, C., Burlina, A., Stevens, R.C., Blau, N., Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency (2008) Hum Mutat, 29, pp. 167-175
Erlandsen, H., Stevens, R.C., The structural basis of phenylketonuria (1999) Mol Genet Metab, 68, pp. 103-125
Guldberg, P., Rey, F., Zschocke, J., Romano, V., François, B., Michiels, L., Ullrich, K., Schmid, H., A European multicenter study of phenylalanine hydroxylase deficiency: Classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype (1998) Am J Hum Genet, 63, pp. 71-79
Pérez-Dueñas, B., Vilaseca, M.A., Mas, A., Lambruschini, N., Artuch, R., Gómez, L., Pineda, J., Campistol, J., Tetrahydrobiopterin responsiveness in patients with phenylketonuria (2004) Clin Biochem, 37, pp. 1083-1090
Muntau, A.C., Röschinger, W., Habich, M., Demmelmair, H., Hoffmann, B., Sommerhoff, C.P., Rosche, A.A., Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria (2002) N Engl J Med, 347, pp. 2122-2132
Fiege, B., Bonafe, L., Ballhausen, D., Baumgartner, M., Thony, B., Meili, D., Fiori, L., Blau, N., Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: A pilot study (2005) Mol Genet Metab, 86, pp. S91-S95
Pey, A.L., Desviat, L.R., Gámez, A., Ugarte, M., Pérez, B., Phenylketonuria: Genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH (2003) Hum Mutat, 21, pp. 70-78
Okano, Y., Asada, M., Kang, Y., Nishi, Y., Hase, Y., Oura, T., Isshiki, G., Molecular characterization of phenylketonuria in Japanese patients (1998) Hum Genet, 103, pp. 613-618
Bercovich, D., Elimelech, A., Zlotogora, J., Korem, S., Yardeni, T., Gal, N., Goldstein, N., Avraham, S., Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene (2008) J Hum Genet, 53, pp. 407-418
Song, F., Qu, Y.J., Zhang, T., Jin, Y.W., Wang, H., Zheng, X.Y., Phenylketonuria mutations in Northern China (2005) Mol Genet Metab, 86, pp. S107-S118
Mallolas, J., Vilaseca, M.A., Campistol, J., Lambruschini, N., Cambra, F.J., Estivill, X., Milà, M., Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: Genotype-phenotype correlation (1999) Hum Genet, 105, pp. 68-73
Pey, A.L., Perez, B., Desviat, L.R., Martinez, A., Aguado, C., Erlandsen, H., Gamez, A., Ugarte, M., Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations (2004) Hum Mutat, 24, pp. 388-399
Waters, P.J., Parniak, M.A., Akerman, B.R., Jones, A.O., Scriver, C.R., Missense mutations in the phenylalanine hydroxylase gene (PAH) can cause accelerated proteolytic turnover of PAH enzyme: A mechanism underlying phenylketonuria (1999) J Inher Metab Dis, 22, pp. 208-212
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 (2001) Mol Genet Metab, 72, pp. 132-143
Erlandsen, H., Pey, A.L., Gamez, A., Perez, B., Desviat, L.R., Aguado, C., Koch, R., Matalon, R., Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations (2004) Proc Natl Acad Sci USA, 101, pp. 16903-16908
Gersting, S.W., Kemter, K.F., Staudigl, M., Messing, D.D., Danecka, M.K., Lagler, F.B., Sommerhoff, C.P., Muntau, A.C., Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability (2008) Am J Hum Genet, 83, pp. 5-17
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
Daniele, A., Di Natale, P., Heparan N-sulfatase: Cysteine 70 plays a role in the enzyme catalysis and processing (2001) FEBS Lett, 505, pp. 445-448
Andersen, O.A., Stokka, A.J., Flatmark, T., Hough, E., 2.0 Å 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
Kobe, B., Jennings, I.G., House, C.M., Michell, B.J., Goodwill, K.E., Santarsiero, B.D., Stevens, R.C., Kemp, B.E., Structural basis of autoregulation of phenylalanine hydroxylase (1999) Nat Struct Biol, 6, pp. 442-448
Fusetti, F., Erlandsen, H., Flatmark, T., Stevens, R.C., Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria (1998) J Biol Chem, 273, pp. 16962-16967
Jones, T.A., Zou, J.-Y., Cowan, S.W., Kjelgaard, M., Improved methods for building protein models in electron density maps and the location of errors in these models (1991) Acta Crystallogr A, 47, pp. 110-119
Scriver, C. R., Kaufman, S., Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th Edn (, pp. 1667-1724. , In: Scriver, C. R., Kaufman, S., Eisensmith, R. C. Woo, S. L. C., eds), pp. McGraw-Hill, New York, N
Scriver, C. R., The PAH gene, phenylketonuria, and a paradigm shift (2007) Hum Mutat, 28, pp. 831-845
Levy, H. L., Milanowski, A., Chakrapani, A., Cleary, M., Lee, P., Trefz, F. K., Whitley, C. B., Bebchuk, J. D., 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., Dobbelaere, D., 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
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
Scriver, C. R., Waters, P. J., Monogenic traits are not simple. Lessons from phenylketonuria (1999) Trends Genet, 15, pp. 267-272
Scriver, C. R., Phenylketonuria-genotypes and phenotype (1991) N Engl J Med, 324, pp. 1280-1281
Trefz, F. K., Burgard, P., K nig, T., Goebel-Schreiner, B., Lichter-Konecki, U., Konecki, D., Schmidt, E., Bickel, H., Genotype-phenotype correlations in phenylketonuria (1993) Clin Chim Acta, 217, pp. 15-21
Fincham, J. R. S., Pateman, J. A., Formation of an enzyme through complementary action of mutant 'Alleles' in separate nuclei in a heterocaryon (1957) Nature, 179, pp. 741-742
Spaapen, L. J. M., Rubio-Gozalbo, M. E., Tetrahydrobiopterine-responsive phenylalanine hydroxylase deficiency, state of the art (2003) Mol Genet Metab, 78, pp. 93-99
Zurfl h, M. R., Zschocke, J., Lindner, M., Feillet, F., Chery, C., Burlina, A., Stevens, R. C., Blau, N., Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency (2008) Hum Mutat, 29, pp. 167-175
P rez-Due as, B., Vilaseca, M. A., Mas, A., Lambruschini, N., Artuch, R., G mez, L., Pineda, J., Campistol, J., Tetrahydrobiopterin responsiveness in patients with phenylketonuria (2004) Clin Biochem, 37, pp. 1083-1090
Muntau, A. C., R schinger, W., Habich, M., Demmelmair, H., Hoffmann, B., Sommerhoff, C. P., Rosche, A. A., Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria (2002) N Engl J Med, 347, pp. 2122-2132
Pey, A. L., Desviat, L. R., G mez, A., Ugarte, M., P rez, B., Phenylketonuria: Genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH (2003) Hum Mutat, 21, pp. 70-78
Song, F., Qu, Y. J., Zhang, T., Jin, Y. W., Wang, H., Zheng, X. Y., Phenylketonuria mutations in Northern China (2005) Mol Genet Metab, 86, pp. S107-S118
Pey, A. L., Perez, B., Desviat, L. R., Martinez, A., Aguado, C., Erlandsen, H., Gamez, A., Ugarte, M., Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations (2004) Hum Mutat, 24, pp. 388-399
Waters, P. J., Parniak, M. A., Akerman, B. R., Jones, A. O., Scriver, C. R., Missense mutations in the phenylalanine hydroxylase gene (PAH) can cause accelerated proteolytic turnover of PAH enzyme: A mechanism underlying phenylketonuria (1999) J Inher Metab Dis, 22, pp. 208-212
Gersting, S. W., Kemter, K. F., Staudigl, M., Messing, D. D., Danecka, M. K., Lagler, F. B., Sommerhoff, C. P., Muntau, A. C., Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability (2008) Am J Hum Genet, 83, pp. 5-17
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
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
Jones, T. A., Zou, J. -Y., Cowan, S. W., Kjelgaard, M., Improved methods for building protein models in electron density maps and the location of errors in these models (1991) Acta Crystallogr A, 47, pp. 110-119
Febs Journal (ISSN: 1742-464x), 2009 Apr; 276(7): 2048-2059.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 3.042, 5-year impact factor: 3.276
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-62149087350&partnerID=40&md5=7130d08828fde13c4335db8d52b99d56
Keywords: Bh4-Responsiveness, Hyperphenylalaninemia, Molecular Epidemiology, Pah Mutation Functional Analysis, Pah Structural Alterations, Phenylketonuria, Phenylalanine 4 Monooxygenase, Adolescent, Adult, Article, Child, Controlled Study, Enzyme Active Site, Enzyme Activity, Exon, Female, Gene Mutation, Genotype Phenotype Correlation, Human, In Vivo Study, Italy, Major Clinical Study, Preschool Child, Priority Journal, Protein Stability, Amino Acid Sequence, Dihydropteridine Reductase, Models, Molecular Sequence Data, Phenylalanine Hydroxylase, Protein Conformation,
Affiliations:
*** IBB - CNR ***
CEINGE-Biotecnologie Avanzate Scarl, Naples, Italy
IRCCS - Fondazione SDN, Naples, Italy
Dipartimento di Scienze per la Salute, Università Del Molise, Campobasso, Italy
Dipartimento di Pediatria, Università di Napoli 'Federico II', Naples, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli 'Federico II', Naples, Italy
CNR - Istituto di Biostrutture e Bioimmagini, Naples, Italy
CEINGE Biotecnologie, Avanzate S.C.a R.l., via Comunale Margherita 482, I-80145 Napoli, Italy
References:
Scriver, C.R., Kaufman, S., Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th Edn (, pp. 1667-1724. , In: Scriver, C.R., Kaufman, S., Eisensmith, R.C. Woo, S.L.C., eds), pp. McGraw-Hill, New York, N
Scriver, C.R., The PAH gene, phenylketonuria, and a paradigm shift (2007) Hum Mutat, 28, pp. 831-845
Giovannini, M., Verduci, M.E., Salvatici, E., Fiori, L., Riva, E., Phenylketonuria: Dietary and therapeutic challenges (2007) J Inherit Metab Dis, 30, pp. 145-152
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 (2006) J Inherit Metab Dis, 29, pp. 38-46
Levy, H.L., Milanowski, A., Chakrapani, A., Cleary, M., Lee, P., Trefz, F.K., Whitley, C.B., Bebchuk, J.D., 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., Dobbelaere, D., 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
Giannattasio, S., Dianzani, I., Lattanzi, P., Spada, M., Romano, V., Calì, F., Andria, G., Piazza, A., Genetic heterogeneity in five Italian regions: Analysis of PAH mutations and minihaplotypes (2001) Hum Hered, 52, pp. 154-159
Zschocke, J., Phenylketonuria mutations in Europe (2003) Hum Mutat, 21, pp. 345-356
Daniele, A., Cardillo, G., Pennino, C., Carbone, M.T., Scognamiglio, D., Correra, A., Pignero, A., Salvatore, F., Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: A 96% detection rate with ten novel mutations (2007) Ann Hum Genet, 71, pp. 185-193
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
Kayaalp, E., Treacy, E., Waters, P.J., Byck, S., Nowacki, P., Scriver, C.R., Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: A metanalysis of genotype-phenotype correlations (1997) Am J Hum Genet, 61, pp. 1309-1317
Scriver, C.R., Waters, P.J., Monogenic traits are not simple. Lessons from phenylketonuria (1999) Trends Genet, 15, pp. 267-272
Okano, Y., Eisensmith, R.C., Güttler, F., Lichter-Konecki, U., Konecki, D.S., Trefz, F.K., Dasovich, M., Lou, H., Molecular basis of phenotypic heterogeneity in phenylketonuria (1991) N Engl J Med, 324, pp. 1232-1238
Scriver, C.R., Phenylketonuria-genotypes and phenotype (1991) N Engl J Med, 324, pp. 1280-1281
Svensson, E., Von Döbeln, U., Eisensmit, R.C., Hagenfeldt, L., Woo, S.L., Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients (1993) Eur J Pediatr, 152, pp. 132-139
Trefz, F.K., Burgard, P., König, T., Goebel-Schreiner, B., Lichter-Konecki, U., Konecki, D., Schmidt, E., Bickel, H., Genotype-phenotype correlations in phenylketonuria (1993) Clin Chim Acta, 217, pp. 15-21
Fincham, J.R.S., Pateman, J.A., Formation of an enzyme through complementary action of mutant 'alleles' in separate nuclei in a heterocaryon (1957) Nature, 179, pp. 741-742
Ponzone, A., Spada, M., Roasio, L., Porta, F., Mussa, A., Ferraris, S., Impact of neonatal protein metabolism and nutrition on screening for phenylketonuria (2008) J Pediatr Gastroenterol Nutr, 46, pp. 561-569
Spaapen, L.J.M., Rubio-Gozalbo, M.E., Tetrahydrobiopterine-responsive phenylalanine hydroxylase deficiency, state of the art (2003) Mol Genet Metab, 78, pp. 93-99
Zurflüh, M.R., Zschocke, J., Lindner, M., Feillet, F., Chery, C., Burlina, A., Stevens, R.C., Blau, N., Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency (2008) Hum Mutat, 29, pp. 167-175
Erlandsen, H., Stevens, R.C., The structural basis of phenylketonuria (1999) Mol Genet Metab, 68, pp. 103-125
Guldberg, P., Rey, F., Zschocke, J., Romano, V., François, B., Michiels, L., Ullrich, K., Schmid, H., A European multicenter study of phenylalanine hydroxylase deficiency: Classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype (1998) Am J Hum Genet, 63, pp. 71-79
Pérez-Dueñas, B., Vilaseca, M.A., Mas, A., Lambruschini, N., Artuch, R., Gómez, L., Pineda, J., Campistol, J., Tetrahydrobiopterin responsiveness in patients with phenylketonuria (2004) Clin Biochem, 37, pp. 1083-1090
Muntau, A.C., Röschinger, W., Habich, M., Demmelmair, H., Hoffmann, B., Sommerhoff, C.P., Rosche, A.A., Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria (2002) N Engl J Med, 347, pp. 2122-2132
Fiege, B., Bonafe, L., Ballhausen, D., Baumgartner, M., Thony, B., Meili, D., Fiori, L., Blau, N., Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: A pilot study (2005) Mol Genet Metab, 86, pp. S91-S95
Pey, A.L., Desviat, L.R., Gámez, A., Ugarte, M., Pérez, B., Phenylketonuria: Genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH (2003) Hum Mutat, 21, pp. 70-78
Okano, Y., Asada, M., Kang, Y., Nishi, Y., Hase, Y., Oura, T., Isshiki, G., Molecular characterization of phenylketonuria in Japanese patients (1998) Hum Genet, 103, pp. 613-618
Bercovich, D., Elimelech, A., Zlotogora, J., Korem, S., Yardeni, T., Gal, N., Goldstein, N., Avraham, S., Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene (2008) J Hum Genet, 53, pp. 407-418
Song, F., Qu, Y.J., Zhang, T., Jin, Y.W., Wang, H., Zheng, X.Y., Phenylketonuria mutations in Northern China (2005) Mol Genet Metab, 86, pp. S107-S118
Mallolas, J., Vilaseca, M.A., Campistol, J., Lambruschini, N., Cambra, F.J., Estivill, X., Milà, M., Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: Genotype-phenotype correlation (1999) Hum Genet, 105, pp. 68-73
Pey, A.L., Perez, B., Desviat, L.R., Martinez, A., Aguado, C., Erlandsen, H., Gamez, A., Ugarte, M., Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations (2004) Hum Mutat, 24, pp. 388-399
Waters, P.J., Parniak, M.A., Akerman, B.R., Jones, A.O., Scriver, C.R., Missense mutations in the phenylalanine hydroxylase gene (PAH) can cause accelerated proteolytic turnover of PAH enzyme: A mechanism underlying phenylketonuria (1999) J Inher Metab Dis, 22, pp. 208-212
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 (2001) Mol Genet Metab, 72, pp. 132-143
Erlandsen, H., Pey, A.L., Gamez, A., Perez, B., Desviat, L.R., Aguado, C., Koch, R., Matalon, R., Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations (2004) Proc Natl Acad Sci USA, 101, pp. 16903-16908
Gersting, S.W., Kemter, K.F., Staudigl, M., Messing, D.D., Danecka, M.K., Lagler, F.B., Sommerhoff, C.P., Muntau, A.C., Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability (2008) Am J Hum Genet, 83, pp. 5-17
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Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy
Hyperphenylalaninemia (Online Mendelian Inheritance in Man (R) database: 261600) is an autosomal recessive disorder mainly due to mutations in the gene for phenylalanine hydroxylase; the most severe form of hyperphenylalaninemia is classic phenylketonuria. We sequenced the entire gene for phenylalanine hydroxylase in 51 unrelated hyperphenylalaninemia patients from Southern Italy. The entire locus was genotyped in 46 out of 51 hyperphenylalaninemia patients, and 32 different disease-causing mutations were identified. The pathologic nature of two novel gene variants, namely, c.707-2delA and p.Q301P, was demonstrated by in vitro studies. c.707-2delA is a splicing mutation that involves the accepting site of exon 7; it causes the complete skipping of exon 7 and results in the truncated p.T236MfsX60 protein. The second gene variant, p.Q301P, has very low residual enzymatic activity (similar to 4.4%), which may be ascribed, in part, to a low expression level (8-10%). Both the decreased enzyme activity and the low expression level are supported by analysis of the 3D structure of the molecule. The putative structural alterations induced by p.Q301P are compatible with protein instability and perturbance of monomer interactions within dimers and tetramers, although they do not affect the catalytic site. In vivo studies showed tetrahydrobiopterin responsiveness in the p.Q301P carrier but not in the c.707-2delA carrier. We next investigated genotype-phenotype correlations and found that genotype was a good predictor of phenotype in 76% of patients. However, genotype-phenotype discordance occurred in approximately 25% of our patients, mainly those bearing mutations p.L48S, p.R158Q, p.R261Q and p.P281L.
Hyperphenylalaninemia (Online Mendelian Inheritance in Man (R) database: 261600) is an autosomal recessive disorder mainly due to mutations in the gene for phenylalanine hydroxylase; the most severe form of hyperphenylalaninemia is classic phenylketonuria. We sequenced the entire gene for phenylalanine hydroxylase in 51 unrelated hyperphenylalaninemia patients from Southern Italy. The entire locus was genotyped in 46 out of 51 hyperphenylalaninemia patients, and 32 different disease-causing mutations were identified. The pathologic nature of two novel gene variants, namely, c.707-2delA and p.Q301P, was demonstrated by in vitro studies. c.707-2delA is a splicing mutation that involves the accepting site of exon 7; it causes the complete skipping of exon 7 and results in the truncated p.T236MfsX60 protein. The second gene variant, p.Q301P, has very low residual enzymatic activity (similar to 4.4%), which may be ascribed, in part, to a low expression level (8-10%). Both the decreased enzyme activity and the low expression level are supported by analysis of the 3D structure of the molecule. The putative structural alterations induced by p.Q301P are compatible with protein instability and perturbance of monomer interactions within dimers and tetramers, although they do not affect the catalytic site. In vivo studies showed tetrahydrobiopterin responsiveness in the p.Q301P carrier but not in the c.707-2delA carrier. We next investigated genotype-phenotype correlations and found that genotype was a good predictor of phenotype in 76% of patients. However, genotype-phenotype discordance occurred in approximately 25% of our patients, mainly those bearing mutations p.L48S, p.R158Q, p.R261Q and p.P281L.
Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy
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Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy
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Esposito G, Imperato MR, Ieno L, Sorvillo R, Benigno V, Parenti G, Parini R, Vitagliano L, Zagari A, Salvatore F
* Hereditary Fructose Intolerance: Functional Study of Two Novel ALDOB Natural Variants and Characterization of a Partial Gene Deletion (367 views)
Hum Mutat (ISSN: 1059-7794, 1098-1004, 1098-1004electronic), 2010 Dec; 31(12): 1294-1303.
Impact Factor: 5.956
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Daniele A, Cardillo G, Pennino C, Carbone MT, Scognamiglio D, Esposito L, Correra A, Castaldo G, Zagari A, Salvatore F
* Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants (347 views)
Bba-Gen Subjects (ISSN: 0925-4439, 0006-3002, 1570-9639), 2008 Jun; 1782(6): 378-384.
Impact Factor: 2.233
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* Hereditary Fructose Intolerance: Functional Study of Two Novel ALDOB Natural Variants and Characterization of a Partial Gene Deletion (367 views)
Hum Mutat (ISSN: 1059-7794, 1098-1004, 1098-1004electronic), 2010 Dec; 31(12): 1294-1303.
Impact Factor: 5.956
View Export to BibTeX Export to EndNote
Daniele A, Cardillo G, Pennino C, Carbone MT, Scognamiglio D, Esposito L, Correra A, Castaldo G, Zagari A, Salvatore F
* Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants (347 views)
Bba-Gen Subjects (ISSN: 0925-4439, 0006-3002, 1570-9639), 2008 Jun; 1782(6): 378-384.
Impact Factor: 2.233
View Export to BibTeX Export to EndNote
2 Records (2 excluding Abstracts).
Total impact factor: 8.189 (8.189 excluding Abstracts).
Total 5 year impact factor: 9.028 (9.028 excluding Abstracts).
Total impact factor: 8.189 (8.189 excluding Abstracts).
Total 5 year impact factor: 9.028 (9.028 excluding Abstracts).
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