ArticleAmerican journal of human genetics2020
Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 3 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 3 syntheses or guidelines pooled it, 95 citations in OpenAlex.
- Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review.International journal of molecular sciences · 2025Pooled it
- MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.Cellular & molecular biology letters · 2025Pooled it
- Exploration of key drug target proteins highlighting their related regulatory molecules, functional pathways and drug candidates associated with delirium: evidence from meta-data analyses.BMC geriatrics · 2023Pooled it
- Clinical consensus guidelines for the management of Noonan syndrome in Japan.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2026Article
- Monoallelic SH2B1 Variants in Neurodevelopmental Disorders: Phenotypic Expansion and Functional Characterization of Rare Variants.Molecular genetics & genomic medicine · 2026Article
- Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice.HGG advances · 2026Article
- Identification and validation of hub genes involved in papillary thyroid carcinoma progression.BMC cancer · 2026Article
- Proteome Microarray-Guided Global View: Multiple Pharmacological Targets of Icariin.Drug design, development and therapy · 2026Article
- Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice.bioRxiv : the preprint server for biology · 2025Article
- Cell-extrinsic controls over neocortical neuron fate and diversity.Science advances · 2025Article
- Article
- A Novel Description of Immunodeficiency and Immune Dysregulation in a 14-Year-Old Girl with Noonan Syndrome 13.Journal of clinical immunology · 2025Article
- Variable Ophthalmologic Phenotypes Associated with Biallelic Loss-of-Function Variants inInternational journal of molecular sciences · 2025Article
- Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.European journal of pediatrics · 2024Article
- ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity.Cell reports · 2024Article
- CDHu40: a novel marker gene set of neuroendocrine prostate cancer.Briefings in bioinformatics · 2024Article
- Biomarker Landscape in RASopathies.International journal of molecular sciences · 2024Review
- Germline bi-allelicHaematologica · 2024Article
- Whole Genome Sequencing Solves an Atypical Form of Bardet-Biedl Syndrome: Identification of Novel Pathogenic Variants ofInternational journal of molecular sciences · 2024Article
- RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.Disease models & mechanisms · 2024Review
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Authors and funding
50 authors at 20 institutions in 5 countries.
Funding
Abstract
Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
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