Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy
Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy(369 views) Daniele A, Scala I, Cardillo G, Pennino C, Ungaro C, Sibilio M, Parenti G, Esposito L, Zagari A, Andria G, Salvatore F
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
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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
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.
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