ArticleAmerican journal of human genetics2021
Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 2 of them syntheses that pooled it.
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Who cites it
65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 96 citations in OpenAlex.
- Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations-A Systematic Review.International journal of molecular sciences · 2026Pooled it
- TMBserval: a statistical explainable learning model reveals weighted tumor mutation burden better categorizing therapeutic benefits.Frontiers in immunology · 2023Pooled it
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- A targeted vector for brain endothelial cell gene delivery and cerebrovascular malformation modelling.Nature biomedical engineering · 2026Article
- Article
- Intramedullary Spinal Cord Cavernous Angiomas in Familial Cerebral Cavernous Malformations.Genes · 2026Review
- CXCL13⁺ CD4⁺ T cells are associated with B-cell recruitment and lesion progression in cerebral cavernous malformations.Journal of neuroinflammation · 2026Article
- Human stem cell models in cerebral cavernous malformations.Stem cell research & therapy · 2026Review
- Knockin expression of human ADAMTS5 impairs cardiovascular development and aggravates cerebral cavernous malformations in mice.Disease models & mechanisms · 2026Article
- MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.Cell death discovery · 2026Review
- The Role of Immune Infiltration and Oxidative Stress in the Progression of Cerebral Cavernous Malformation.Brain and behavior · 2026Review
- Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.Journal of neurochemistry · 2026Review
- TLNRD1-CCM2 interaction maintains endothelial actin networks through a KLF2/4-independent mechanism.JVS-vascular science · 2026Article
- Integration of artificial intelligence and high-content screening enabled identification of drugs for long-term treatment of cerebral cavernous malformation disease.bioRxiv : the preprint server for biology · 2025Article
- Clinical Significance of Somatic PIK3CA and MAP3K3 Mutations in Cerebral and Spinal Cavernous Malformations.Translational stroke research · 2025Article
- Late-onset familial cerebral cavernous malformation without a family history: a case description.Quantitative imaging in medicine and surgery · 2025Article
- Unraveling Etiological Indications and Therapeutic Implications of Familial Cerebral Cavernous Malformations in the Dawn of Gene Therapy for Monogenic Conditions.Current gene therapy · 2025Article
- Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.Human molecular genetics · 2025Article
- The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis.Journal of clinical medicine · 2025Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cerebral cavernous malformations (CCMs) are vascular disorders that affect up to 0.5% of the total population. About 20% of CCMs are inherited because of familial mutations in CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10, whereas the etiology of a majority of simplex CCM-affected individuals remains unclear. Here, we report somatic mutations of MAP3K3, PIK3CA, MAP2K7, and CCM genes in CCM lesions. In particular, somatic hotspot mutations of PIK3CA are found in 11 of 38 individuals with CCMs, and a MAP3K3 somatic mutation (c.1323C>G [p.Ile441Met]) is detected in 37.0% (34 of 92) of the simplex CCM-affected individuals. Strikingly, the MAP3K3 c.1323C>G mutation presents in 95.7% (22 of 23) of the popcorn-like lesions but only 2.5% (1 of 40) of the subacute-bleeding or multifocal lesions that are predominantly attributed to mutations in the CCM1/2/3 signaling complex. Leveraging mini-bulk sequencing, we demonstrate the enrichment of MAP3K3 c.1323C>G mutation in CCM endothelium. Mechanistically, beyond the activation of CCM1/2/3-inhibited ERK5 signaling, MEKK3 p.Ile441Met (MAP3K3 encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement. Collectively, we identified several somatic activating mutations in CCM endothelium, and the MAP3K3 c.1323C>G mutation defines a primary CCM subtype with distinct characteristics in signaling activation and magnetic resonance imaging appearance.
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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.