ArticleeLife2019
Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
39 citing papers in PubMed, 73 citations in OpenAlex.
- Hereditary diffuse gastric cancer in progress: Comparative lessons from Lynch syndrome.European journal of human genetics : EJHG · 2026Review
- Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.Nature communications · 2026Article
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Article
- MAVISp: A modular structure-based framework for protein variant effects.Protein science : a publication of the Protein Society · 2026Article
- Supervised learning of protein variant effects across large-scale mutagenesis datasets.Protein science : a publication of the Protein Society · 2026Article
- MutAnt: mutation annotation tool predicts deleteriousness of missense mutations and improves mutation calling from transcriptomics.Human genetics · 2025Article
- Disentangling the mutational effects on protein stability and interaction of human MLH1.PLoS genetics · 2025Article
- Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.DNA repair · 2025Article
- VarMeter2: An enhanced structure-based method for predicting pathogenic missense variants through Mahalanobis distance.Computational and structural biotechnology journal · 2025Article
- Reclassification of Two MLH1 Variants of Uncertain Significance Utilizing Clinical and Functional Data.Molecular genetics & genomic medicine · 2024Article
- Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.bioRxiv : the preprint server for biology · 2024Article
- The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1.The Journal of biological chemistry · 2024Article
- Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease.American journal of human genetics · 2024Article
- Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants.Nature communications · 2024Article
- Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.Genome biology · 2024Article
- A mutational atlas for Parkin proteostasis.Nature communications · 2024Article
- Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.Molecular biology of the cell · 2023Article
- Mutations observed in somatic evolution reveal underlying gene mechanisms.Communications biology · 2023Article
- Interpreting the molecular mechanisms of disease variants in human transmembrane proteins.Biophysical journal · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying many
Indexed as
Identifiers
What OpenQuestion holds
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.