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.
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 HPApatients, 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.
Authors: Alicia Hillert; Yair Anikster; Amaya Belanger-Quintana; Alberto Burlina; Barbara K Burton; Carla Carducci; Ana E Chiesa; John Christodoulou; Maja Đorđević; Lourdes R Desviat; Aviva Eliyahu; Roeland A F Evers; Lena Fajkusova; François Feillet; Pedro E Bonfim-Freitas; Maria Giżewska; Polina Gundorova; Daniela Karall; Katya Kneller; Sergey I Kutsev; Vincenzo Leuzzi; Harvey L Levy; Uta Lichter-Konecki; Ania C Muntau; Fares Namour; Mariusz Oltarzewski; Andrea Paras; Belen Perez; Emil Polak; Alexander V Polyakov; Francesco Porta; Marianne Rohrbach; Sabine Scholl-Bürgi; Norma Spécola; Maja Stojiljković; Nan Shen; Luiz C Santana-da Silva; Anastasia Skouma; Francjan van Spronsen; Vera Stoppioni; Beat Thöny; Friedrich K Trefz; Jerry Vockley; Youngguo Yu; Johannes Zschocke; Georg F Hoffmann; Sven F Garbade; Nenad Blau Journal: Am J Hum Genet Date: 2020-07-14 Impact factor: 11.025