Hyperphenylalaninemia in the Czech Republic: Genotype-phenotype correlations and in silico analysis of novel missense mutations

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Authors

RÉBLOVÁ Kamila HRUBÁ Zuzana PROCHÁZKOVÁ Dagmar PAZDÍRKOVÁ Renata POUCHLÁ Slávka FAJKUSOVÁ Lenka

Year of publication 2013
Type Article in Periodical
Magazine / Source Clinica Chimica Acta
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://www.sciencedirect.com/science/article/pii/S0009898113000211
Doi http://dx.doi.org/10.1016/j.cca.2013.01.006
Field Oncology and hematology
Keywords Hyperphenylalaninemia; molecular modelling; phenylalanine hydroxylase
Attached files
Description Abstract BACKGROUND: Hyperphenylalaninemia (HPA) is one of the most common inherited metabolic disorders caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). HPA is associated with mutations in the PAH gene, which leads to reduced protein stability and/or impaired catalytic function. Currently, almost 700 different disease-causing mutations have been described. The impact of mutations on enzyme activity varies ranging from classical PKU, mild PKU, to non-PKU HPA phenotype. METHODS: We provide results of molecular genetic diagnostics of 665 Czech unrelated HPA patients, structural analysis of missense mutations associated with classical PKU and non-PKU HPA phenotype, and prediction of effects of 6 newly discovered HPA missense mutations using bioinformatic approaches and Molecular Dynamics simulations. RESULTS: Ninety-eight different types of mutations were indentified. Thirteen of these were novel (6 missense, 2 nonsense, 1 splicing, and 4 small gene rearrangements). Structural analysis revealed that classical PKU mutations are more non-conservative compared to non-PKU HPA mutations and that specific sequence and structural characteristics of a mutation might be critical when distinguishing between non-PKU HPA and classical PKU mutations. The greatest impact was predicted for the p.(Phe263Ser) mutation while other novel mutations p.(Asn167Tyr), p.(Thr200Asn), p.(Asp229Gly), p.(Leu358Phe), and p.(Ile406Met) were found to be less deleterious
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