ArticleProceedings of the National Academy of Sciences of the United States of America2017
In vivo severity ranking of Ras pathway mutations associated with developmental disorders.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 64 citations in OpenAlex.
- SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly.American journal of medical genetics. Part A · 2026Article
- Applications and challenges of Drosophila melanogaster as a laboratory model in human cancer research: a narrative review.Discover oncology · 2025Review
- Optogenetics with Atomic Precision─A Comprehensive Review of Optical Control of Protein Function through Genetic Code Expansion.Chemical reviews · 2025Review
- A Drug Discovery Pipeline for MAPK/ERK Pathway Inhibitors in Caenorhabditis elegans.Cancer research communications · 2024Article
- Non-Mammalian Models for Understanding Neurological Defects in RASopathies.Biomedicines · 2024Review
- Assessment of the FRET-based Teen sensor to monitor ERK activation changes preceding morphological defects in a RASopathy zebrafish model and phenotypic rescue by MEK inhibitor.Molecular medicine (Cambridge, Mass.) · 2024Article
- A guide to ERK dynamics, part 2: downstream decoding.The Biochemical journal · 2023Article
- Activating mutations drive human MEK1 kinase using a gear-shifting mechanism.The Biochemical journal · 2023Article
- Evolutionary history of MEK1 illuminates the nature of deleterious mutations.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Genetically Encoded Aminocoumarin Lysine for Optical Control of Protein-Nucleotide Interactions in Zebrafish Embryos.ACS chemical biology · 2023Article
- Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.Science advances · 2023Article
- Stochastic phenotypes in RAS-dependent developmental diseases.Current biology : CB · 2023Article
- Diverse Clinical Manifestations of Cardiofaciocutaneous Syndrome Type 3 in Two Patients from South East Asia.Molecular syndromology · 2023Article
- RASopathy mutations provide functional insight into the BRAF cysteine-rich domain and reveal the importance of autoinhibition in BRAF regulation.Molecular cell · 2022Article
- Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome.Human molecular genetics · 2022Article
- The Zebrafish model in dermatology: an update for clinicians.Discover oncology · 2022Review
- Article
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.American journal of human genetics · 2021Article
- The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair.Journal of cell science · 2021Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.
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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.