ArticleAmerican journal of human genetics2007
Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.
Article in American journal of human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84 citing papers in PubMed, 179 citations in OpenAlex.
- Neonatal genetic sequencing as a first-tier option: a real-world clinical implementation study in Northern China.Annals of medicine · 2026Article
- Mapping the Severity of Phenylalanine Hydroxylase Deficiency.Journal of inherited metabolic disease · 2026Review
- Supervised learning of protein variant effects across large-scale mutagenesis datasets.Protein science : a publication of the Protein Society · 2026Article
- Therapeutic effect of histone deacetylase 6 inhibitor for a mouse model of phenylketonuria.Scientific reports · 2025Article
- Systematic evaluation of predictors for binding free energy changes upon mutations in protein complexes.Briefings in bioinformatics · 2025Article
- Missense Variants in Nutrition-Related Genes: A Computational Study.International journal of molecular sciences · 2025Article
- Endoplasmic reticulum stress pathways and cellular death mechanisms in patients with phenylketonuria.Molecular biology reports · 2025Article
- When "loss-of-function" means proteostasis burden: Thinking again about coding DNA variants.American journal of human genetics · 2025Article
- Linking Protein Stability to Pathogenicity: Predicting Clinical Significance of Single-Missense Mutations in Ocular Proteins Using Machine Learning.International journal of molecular sciences · 2024Article
- Delays in Newborn Screening for Phenylketonuria from Birth to Diagnosis and Factors Affecting This.Children (Basel, Switzerland) · 2024Article
- Genetic Landscape and Clinical Features of Hyperphenylalaninemia in North Ossetia-Alania: High Frequency of P281L and P211T Genetic Variants in theInternational journal of molecular sciences · 2024Article
- Interpreting the molecular mechanisms of disease variants in human transmembrane proteins.Biophysical journal · 2023Article
- Lynch syndrome, molecular mechanisms and variant classification.British journal of cancer · 2023Review
- Phosphorylation of Thr9 Affects the Folding Landscape of the N-Terminal Segment of Human AGT Enhancing Protein Aggregation of Disease-Causing Mutants.Molecules (Basel, Switzerland) · 2022Article
- Characterization of phenylalanine hydroxylase gene variants and analysis of genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China.Molecular biology reports · 2022Article
- Genome interpretation using in silico predictors of variant impact.Human genetics · 2022Review
- Follow-up of two newborns with c.158G>A (p.Arg53His) mutation in gene and assessment of the site function.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2021Article
- Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase.International journal of molecular sciences · 2021Article
- Mapping the degradation pathway of a disease-linked aspartoacylase variant.PLoS genetics · 2021Article
- Galactosemia: Towards Pharmacological Chaperones.Journal of personalized medicine · 2021Review
24 more citing papers are in PubMed but not listed here.
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4 authors at 2 institutions in 2 countries.
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Abstract
Phenylketonuria (PKU) is a genetic disease caused by mutations in human phenylalanine hydroxylase (PAH). Most missense mutations result in misfolding of PAH, increased protein turnover, and a loss of enzymatic function. We studied the prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, using the protein-design algorithm FoldX. For the 80 mutations for which expression analyses have been performed in eukaryote systems, in most cases we found substantial overall correlations between the mutational energetic impact and both in vitro residual activities and patient metabolic phenotype. This finding confirmed that the decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome. Metabolic phenotypes have been shown to be better predicted than in vitro residual activities, probably because of greater stringency in the phenotyping process. Finally, all the remaining 238 PKU missense mutations compiled at the PAH locus knowledgebase (PAHdb) were analyzed, and their phenotypic outcomes were predicted on the basis of the energetic impact provided by FoldX. Residues in exons 7-9 and in interdomain regions within the subunit appear to play an important structural role and constitute hotspots for destabilization. FoldX analysis will be useful for predicting the phenotype associated with rare or new mutations detected in patients with PKU. However, additional factors must be considered that may contribute to the patient phenotype, such as possible effects on catalysis and interindividual differences in physiological and metabolic processes.
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