ArticleProteins2012
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.
Article in Proteins, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Genetic diagnosis and molecular characterization of three novel variations in the phenylalanine hydroxylase gene from Chinese patients with phenylketonuria.EXCLI journal · 2026Article
- Detection of Single-Nucleotide and Copy Number Defects Underlying Hyperphenylalaninemia by Next-Generation Sequencing.Biomedicines · 2023Article
- Functional Impact of a Cancer-Related Variant in Human ΔACS omega · 2023Article
- Functional Analyses of Rare Germline MissenseGenes · 2023Article
- Solvent accessibility of E1α and E1β residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC-E1 structure and function.Journal of inherited metabolic disease · 2022Article
- Protein Degradation and the Pathologic Basis of Phenylketonuria and Hereditary Tyrosinemia.International journal of molecular sciences · 2020Review
- Animal Model Contributions to Congenital Metabolic Disease.Advances in experimental medicine and biology · 2020Review
- β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice.The Journal of biological chemistry · 2019Article
- Systems Biology and Multi-Omics Integration: Viewpoints from the Metabolomics Research Community.Metabolites · 2019Article
- New protein structures provide an updated understanding of phenylketonuria.Molecular genetics and metabolism · 2017Review
- 129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant.Molecular and cellular biology · 2015Article
- Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies.Journal of molecular biology · 2015Article
- Insights from GWAS: emerging landscape of mechanisms underlying complex trait disease.BMC genomics · 2015Article
- Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency.Human mutation · 2014Article
- Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model.Journal of neurochemistry · 2014Article
- Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
A previous computational analysis of missense mutations linked to monogenic disease found a high proportion of missense mutations affect protein stability, rather than other aspects of protein structure and function. The purpose of this study is to relate the presence of such stability damaging missense mutations to the levels of a particular protein present under "in vivo" like conditions, and to test the reliability of the computational methods. Experimental data on a set of missense mutations of the enzyme phenylalanine hydroxylase (PAH) associated with the monogenic disease phenylketonuria (PKU) have been compared with the expected in vivo impact on protein function, obtained using SNPs3D, an in silico analysis package. A high proportion of the PAH mutations are predicted to be destabilizing. The overall agreement between predicted stability impact and experimental evidence for lower protein levels is in accordance with the estimated error rates of the methods. For these mutations, destabilization of protein three-dimensional structure is the major molecular mechanism leading to PKU, and results in a substantial reduction of in vivo PAH protein concentration. Although of limited scale, the results support the view that destabilization is the most common mechanism by which missense mutations cause monogenic disease. In turn, this conclusion suggests the general therapeutic strategy of developing drugs targeted at restoring wild type stability.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.