Home Ricerca Sedi Chi siamo Organigramma Personale Contatti Didattica Login Documenti EN
Progetti in evidenza
INCIPIT
(Link esterno)

ISTAPCA
(1204 visite)

Fondo Europeo Pesca
(614 visite)

Euro-BioImaging
(Link esterno)

Fondazione Veronesi
(Link esterno)

LightDyNAmics
(1082 visite)

 INMiND
(1179 visite)

Instruct-IT
(Link esterno)

 PRIN
(1320 visite)

 eHealthNet
(1083 visite)

Ponrec
(1025 visite)

MFAG Grant
(1126 visite)

MERIT
(Link esterno)


Collegamenti

Contiene: [X]      Estesa     Autori: [X]  Tipo di lavoro: [X]
Data iniziale: Data finale: [X]      Sede: Affiliazione IBB     
    
[Pulisci modulo]



Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy (103 visite)

Daniele A, Scala I, Cardillo G, Pennino C, Ungaro C, Sibilio M, Parenti G, Esposito L, Zagari A, Andria G, Salvatore F

Febs Journal (ISSN: 1742-464x), 2009 Apr; 276(7): 2048-2059.

Tipo di articolo: Journal Article, , Impact factor: 3.042, Impact factor a 5 anni: 3.276, Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-62149087350&partnerID=40&md5=7130d08828fde13c4335db8d52b99d56

Parole chiave: 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,

Affiliazioni: *** 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


Riferimenti: 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

Svensson, E., Von D beln, 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., 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



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.
Nessun risultato.
Nessun risultato.

Contiene: [X]      Estesa     Autori: [X]  Tipo di lavoro: [X]
Data iniziale: Data finale: [X]      Sede: Affiliazione IBB     
    
[Pulisci modulo]


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 (103 visite)
Biochim Biophys Acta (ISSN: 0925-4439, 0006-3002, 1570-9639), 2008 Jun; 1782(6): 378-384.
Impact Factor: 2.233
Dettagli    Esporta in BibTeX    Esporta in EndNote



1 Records (1 escludendo Abstract e Conferenze).
Impact factor totale: 2.233 (2.233 escludendo Abstract e Conferenze).
Impact factor a 5 anni totale: 2.816 (2.816 escludendo Abstract e Conferenze).







    Esporta in BibTeX    Esporta in EndNote

Ultima modifica di Marco Comerci in data Thursday 19 March 2015, 14:24:23
103 visite. Ultima visita in data Saturday 08 December 2018, 15:42:33

Webmaster and developer: Marco Comerci
Per problemi e suggerimenti: adminibb.cnr.it
Ultimo aggiornamento: Tuesday 11 December 2018, 12:37:42