Computational study of missense mutations in phenylalanine hydroxylase

Journal of Molecular Modeling
Kamila RéblováLenka Fajkusová

Abstract

Hyperphenylalaninemia (HPA) is one of the most common metabolic disorders. HPA, which is transmitted by an autosomal recessive mode of inheritance, is caused by mutations of the phenylalanine hydroxylase gene. Most mutations are missense and lead to reduced protein stability and/or impaired catalytic function. The impact of such mutations varies, ranging from classical phenylketonuria (PKU), mild PKU, to non-PKU HPA phenotypes. Despite the fact that HPA is a monogenic disease, clinical data show that one PKU genotype can be associated with more in vivo phenotypes, which indicates the role of other (still unknown) factors. To better understand the phenotype-genotype relationships, we analyzed computationally the impact of missense mutations in homozygotes stored in the BIOPKU database. A total of 34 selected homozygous genotypes was divided into two main groups according to their phenotypes: (A) genotypes leading to non-PKU HPA or combined phenotype non-PKU HPA/mild PKU and (B) genotypes leading to classical PKU, mild PKU or combined phenotype mild PKU/classical PKU. Combining in silico analysis and molecular dynamics simulations (in total 3 μs) we described the structural impact of the mutations, which allowed us to separate 32...Continue Reading

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Citations

Feb 18, 2016·Proceedings of the National Academy of Sciences of the United States of America·Emilia C ArturoEileen K Jaffe
Oct 2, 2015·Aging and Disease·Patrícia Fernanda SchuckGustavo Costa Ferreira
Jan 11, 2017·Human Mutation·Abhishek Niroula, Mauno Vihinen
May 3, 2019·Orphanet Journal of Rare Diseases·Romana BorskáLenka Fajkusová
Feb 20, 2020·Revista paulista de pediatria : orgão oficial da Sociedade de Pediatria de São Paulo·Roseli Divino CostaMarcial Francis Galera
Jul 23, 2020·Frontiers in Genetics·Lucie DuškováLenka Fajkusová

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