ArticleJournal of molecular evolution2016
Protein Destabilization as a Common Factor in Diverse Inherited Disorders.
Article in Journal of molecular evolution, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 76 citations in OpenAlex.
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- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID.Nature communications · 2025Article
- A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system.Disease models & mechanisms · 2025Article
- A quantitative comparison of the deleteriousness of missense and nonsense mutations using the structurally resolved human protein interactome.Protein science : a publication of the Protein Society · 2025Article
- ACMG/AMP interpretation of BRCA1 missense variants: Structure-informed scores add evidence strength granularity to the PP3/BP4 computational evidence.American journal of human genetics · 2025Article
- Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function.Nature communications · 2025Article
- Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions.Nature communications · 2025Article
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- Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.Genome biology · 2024Article
- Multiplexed Functional Assessments ofCirculation. Genomic and precision medicine · 2024Article
- Identification and mechanism determination of the efflux pump subunit amrB gene mutations linked to gentamicin susceptibility in clinical Burkholderia pseudomallei from Malaysian Borneo.Molecular genetics and genomics : MGG · 2024Article
- Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease.Frontiers in cardiovascular medicine · 2024Review
- Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.Molecular biology of the cell · 2023Article
- Genome mining yields putative disease-associated ROMK variants with distinct defects.PLoS genetics · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Protein destabilization by amino acid substitutions is proposed to play a prominent role in widespread inherited human disorders, not just those known to involve protein misfolding and aggregation. To test this hypothesis, we computationally evaluate the effects on protein stability of all possible amino acid substitutions in 20 disease-associated proteins with multiple identified pathogenic missense mutations. For 18 of the 20 proteins studied, substitutions at known positions of pathogenic mutations are significantly more likely to destabilize the native protein fold (as indicated by more positive values of ∆∆G). Thus, positions identified as sites of disease-associated mutations, as opposed to non-disease-associated sites, are predicted to be more vulnerable to protein destabilization upon amino acid substitution. This finding supports the notion that destabilization of native protein structure underlies the pathogenicity of broad set of missense mutations, even in cases where reduced protein stability and/or aggregation are not characteristic of the disease state.
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Registered trials
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.