Abstract
Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive disease, caused by mutations in the Phenylalanine Hydroxylase (PAH) gene situated in chromosome 12q22-q24.2. This gene has 13 exons. To date, 991 mutations have been described. The genotype is one of the main factors that determine the phenotype of this disease. Objective: Characterize PKU genotype and phenotype seen in Chilean PKU patients. Methods: We studied the PAH gene by restriction fragment length polymorphism (RFLP) and/or sequencing techniques to identify pathogenic mutations in 71 PKU subjects. We classified the phenotype according to Guldberg predicted value. Results: We identified 26 different mutations in 134 of the 142 alleles studied (94.4%), 88.7% of the subjects had biallelic pathogenic mutations while 11.3% had only one pathogenic mutation identified. Compound heterozygous represented 85.9% of the cases. Exon 7 included the majority of mutations (26.9%) and 50% of mutations were missense. The most frequent mutations were c.1066-11G > A, c.442-?_509+?del and p.Val388Met. The majority of subjects (52.3%) had the classic phenotype. Conclusions: The most frequent mutations in our Chilean PKU population were p.Val388Met, c.442?_509+?del and c.1066-11G > A. It is possible to predict phenotype by detecting the genotype, and use this information to determine disease prognosis and adjust patient’s medical and nutritional management accordingly.
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References
Aldamiz-Echevarria L, Llarena M, Bueno MA, Dalmau J, Vitoria I, Fernandez-Marmiesse A, Andrade F, Blasco J, Alcalde C, Gil D, Garcia MC, Gonzalez-Lamuno D, Ruiz M, Ruiz MA, Pena-Quintana L, Gonzalez D, Sanchez-Valverde F, Desviat LR, Perez B, Couce ML (2016) Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. J Hum Genet 61(8):731–744
Blau N (2016) Genetics of phenylketonuria: then and now. Hum Mutat 37(6):508–515
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U (2011) Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 104(Suppl):S2–S9
Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, Coates PM, Cunningham AC, Dobrowolski SF, Ferguson JH, Franklin TD, Frazier DM, Grange DK, Greene CL, Groft SC, Harding CO, Howell RR, Huntington KL, Hyatt-Knorr HD, Jevaji IP, Levy HL, Lichter-Konecki U, Lindegren ML, Lloyd-Puryear MA, Matalon K, MacDonald A, McPheeters ML, Mitchell JJ, Mofidi S, Moseley KD, Mueller CM, Mulberg AE, Nerurkar LS, Ogata BN, Pariser AR, Prasad S, Pridjian G, Rasmussen SA, Reddy UM, Rohr FJ, Singh RH, Sirrs SM, Stremer SE, Tagle DA, Thompson SM, Urv TK, Utz JR, van Spronsen F, Vockley J, Waisbren SE, Weglicki LS, White DA, Whitley CB, Wilfond BS, Yannicelli S, Young JM (2014) Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab 112(2):87–122
Cornejo V, Raimann E, Cabello JF, Valiente A, Becerra C, Opazo M, Colombo M (2010) Past, present and future of newborn screening in Chile. J Inherit Metab Dis 33(Suppl 3):S301–S306
Desviat LR, Perez B, De Lucca M, Cornejo V, Schmidt B, Ugarte M (1995) Evidence in Latin America of recurrence of V388M, a phenylketonuria mutation with high in vitro residual activity. Am J Hum Genet 57(2):337–342
Gamez A, Perez B, Ugarte M, Desviat LR (2000) Expression analysis of phenylketonuria mutations. Effect on folding and stability of the phenylalanine hydroxylase protein. J Biol Chem 275(38):29737–29742
Gizewska M, MacDonald A, Belanger-Quintana A, Burlina A, Cleary M, Coskun T, Feillet F, Muntau AC, Trefz FK, van Spronsen FJ, Blau N (2016) Diagnostic and management practices for phenylketonuria in 19 countries of the South and Eastern European Region: survey results. Eur J Pediatr 175(2):261–272
Greene CL, Longo N (2014) National Institutes of Health (NIH) review of evidence in phenylalanine hydroxylase deficiency (phenylketonuria) and recommendations/guidelines for therapy from the American College of Medical Genetics (ACMG) and Genetics Metabolic Dietitians International (GMDI). Mol Genet Metab 112(2):85–86
Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Guttler F (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63(1):71–79
Leandro P, Rivera I, Lechner MC, de Almeida IT, Konecki D (2000) The V388M mutation results in a kinetic variant form of phenylalanine hydroxylase. Mol Genet Metab 69(3):204–212
Leandro J, Nascimento C, de Almeida IT, Leandro P (2006) Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim Biophys Acta 1762(5):544–550
Mitchell JJ Jr (2011) The findings of the Dartmouth Atlas Project: a challenge to clinical and ethical excellence in end-of-life care. J Clin Ethics 22(3):267–276
Pey AL, Desviat LR, Gamez A, Ugarte M, Perez B (2003) Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 21(4):370–378
Santos LL, Castro-Magalhaes M, Fonseca CG, Starling AL, Januario JN, Aguiar MJ, Carvalho MR (2008) PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet 72(Pt 6):774–779
Scriver CR (2007) The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat 28(9):831–845
Scriver CR, Waters PJ (1999) Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 15(7):267–272
Singh RH, Cunningham AC, Mofidi S, Douglas TD, Frazier DM, Hook DG, Jeffers L, McCune H, Moseley KD, Ogata B, Pendyal S, Skrabal J, Splett PL, Stembridge A, Wessel A, Rohr F (2016) Updated, web-based nutrition management guideline for PKU: an evidence and consensus based approach. Mol Genet Metab 118(2):72–83
Trujillano D, Perez B, Gonzalez J, Tornador C, Navarrete R, Escaramis G, Ossowski S, Armengol L, Cornejo V, Desviat LR, Ugarte M, Estivill X (2014) Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing. Eur J Hum Genet 22(4):528–534
Vela-Amieva M, Abreu-Gonzalez M, Gonzalez-del Angel A, Ibarra-Gonzalez I, Fernandez-Lainez C, Barrientos-Rios R, Monroy-Santoyo S, Guillen-Lopez S, Alcantara-Ortigoza MA (2015) Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect. Clin Genet 88(1):62–67
Waters PJ (2003) How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. Hum Mutat 21(4):357–369
Werner ER, Blau N, Thony B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438(3):397–414
Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N (2015) Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria. Eur J Hum Genet 23(3):302–309
Zschocke J (2008) Dominant versus recessive: molecular mechanisms in metabolic disease. J Inherit Metab Dis 31(5):599–618
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Communicated by: Nenad Blau, PhD
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Valerie Hamilton, Lorena Santa María, Karen Fuenzalida, Paulina Morales, Verónica Cornejo, Belén Pérez, Magdalena Ugarte, and Lourdes Desviat declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). The IRB and the Institute of Nutrition and Food Technologies (INTA) approved a waiver of consent for registries and chart reviews.
Details of the contributions of individual authors:
Valerie Hamilton contributed to the study conception and design; acquisition, analysis and interpretation of the data, drafting of the manuscript and patient follow-up.
Karen Fuenzalida contributed to the study conception and analysis of the data.
Paulina Morales contributed to the study conception.
Lorena Santa María contributed to the study conception and design, acquisition, analysis and interpretation of the data, and revising the manuscript.
Juan Francisco Cabello contributed to revising the manuscript and patient follow-up.
Verónica Cornejo contributed to acquisition of the study and patient follow-up.
Belén Pérez contributed to the study conception, analysis of the data, and revising the manuscript.
Magdalena Ugarte contributed revising the manuscript.
Lourdes Desviat contributed revising the manuscript.
All authors gave approval of the final manuscript.
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Hamilton, V. et al. (2018). Characterization of Phenyalanine Hydroxylase Gene Mutations in Chilean PKU Patients. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 42. JIMD Reports, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_85
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DOI: https://doi.org/10.1007/8904_2017_85
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