ArticleNature communications2022
Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 180 papers.
What it found
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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.
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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.
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Who cites it
180 citing papers in PubMed, 289 citations in OpenAlex.
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- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- AlphaMissense prediction for the evaluation of missense variants in the diagnostic setting of neuromuscular disorders.Journal of neuromuscular diseases · 2026Article
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- Melanoma-patient-derived xenograft multi-omics resource melPDomiX maps gain- and loss-of-function alterations.Cell reports · 2026Article
- Disease-associated genetic variants can cause missense effects in tissue-specific protein isoforms.Nature communications · 2026Article
- Functional dissection ofProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Actually, what is a gain-of-function mutation?Genetics · 2026Article
- The role of PPP2R1A variants in gynecologic malignancies: a paradigm shift in immuno-oncology.Journal of translational medicine · 2026Review
- Preserved bone mineral density in autosomal dominant SP7-related osteogenesis imperfecta: a case report of the p.Glu340Ala variant.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
120 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Taking protein structure into account has therefore provided great insight into the molecular mechanisms underlying human genetic disease. While there has been much focus on how mutations can disrupt protein structure and thus cause a loss of function (LOF), alternative mechanisms, specifically dominant-negative (DN) and gain-of-function (GOF) effects, are less understood. Here, we investigate the protein-level effects of pathogenic missense mutations associated with different molecular mechanisms. We observe striking differences between recessive vs dominant, and LOF vs non-LOF mutations, with dominant, non-LOF disease mutations having much milder effects on protein structure, and DN mutations being highly enriched at protein interfaces. We also find that nearly all computational variant effect predictors, even those based solely on sequence conservation, underperform on non-LOF mutations. However, we do show that non-LOF mutations could potentially be identified by their tendency to cluster in three-dimensional space. Overall, our work suggests that many pathogenic mutations that act via DN and GOF mechanisms are likely being missed by current variant prioritisation strategies, but that there is considerable scope to improve computational predictions through consideration of molecular disease mechanisms.
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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.