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Statements

Subject Item
n2:RIV%2F00064173%3A_____%2F13%3A%230000374%21RIV14-MZ0-00064173
rdf:type
skos:Concept n15:Vysledek
dcterms:description
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. 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.
dcterms:title
Hyperphenylalaninemia in the Czech Republic: Genotype-phenotype correlations and in silico analysis of novel missense mutations Hyperphenylalaninemia in the Czech Republic: Genotype-phenotype correlations and in silico analysis of novel missense mutations
skos:prefLabel
Hyperphenylalaninemia in the Czech Republic: Genotype-phenotype correlations and in silico analysis of novel missense mutations Hyperphenylalaninemia in the Czech Republic: Genotype-phenotype correlations and in silico analysis of novel missense mutations
skos:notation
RIV/00064173:_____/13:#0000374!RIV14-MZ0-00064173
n15:predkladatel
n16:ico%3A00064173
n3:aktivita
n9:I n9:P n9:V
n3:aktivity
I, P(ED1.1.00/02.0068), P(EE2.3.20.0045), V
n3:cisloPeriodika
18 April
n3:dodaniDat
n7:2014
n3:domaciTvurceVysledku
n17:1557726
n3:druhVysledku
n4:J
n3:duvernostUdaju
n12:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
78545
n3:idVysledku
RIV/00064173:_____/13:#0000374
n3:jazykVysledku
n19:eng
n3:klicovaSlova
Molecular modelling; Genotype-phenotype relationship; Phenylalanine hydroxylase; Hyperphenylalaninemia
n3:klicoveSlovo
n5:Genotype-phenotype%20relationship n5:Hyperphenylalaninemia n5:Molecular%20modelling n5:Phenylalanine%20hydroxylase
n3:kodStatuVydavatele
NL - Nizozemsko
n3:kontrolniKodProRIV
[FF5C2979B7DB]
n3:nazevZdroje
Clinica Chimica Acta
n3:obor
n13:EB
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
7
n3:projekt
n14:ED1.1.00%2F02.0068 n14:EE2.3.20.0045
n3:rokUplatneniVysledku
n7:2013
n3:svazekPeriodika
419
n3:tvurceVysledku
Pazdírková, Renáta
n3:wos
000318192700001
s:issn
0009-8981
s:numberOfPages
11
n8:doi
10.1016/j.cca.2013.01.006