ArticleBrain : a journal of neurology2023
Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06091332 (Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus), which is not on this map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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.
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.
Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Randomized, Placebo-controlled Pilot Trial
Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations-A Systematic Review.International journal of molecular sciences · 2026Pooled it
- Genetic and immunologic determinants of BCG disease: from mechanism to prevention.Annals of medicine · 2026Review
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MicroRNA-21-3p regulation of NADPH oxidase 4 and vascular endothelial growth factor A contributes to hemorrhage in cerebral cavernous malformations.Non-coding RNA research · 2026Article
- A targeted vector for brain endothelial cell gene delivery and cerebrovascular malformation modelling.Nature biomedical engineering · 2026Article
- Multimodal MRI habitat atlas for personalised re-haemorrhage risk prediction in brainstem cavernous malformations.Stroke and vascular neurology · 2026Article
- Article
- Intramedullary Spinal Cord Cavernous Angiomas in Familial Cerebral Cavernous Malformations.Genes · 2026Review
- MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.Cell death discovery · 2026Review
- Recurrent somatic copy number alterations in resected cerebral cavernous malformations.Human genomics · 2025Article
- Epidural cavernous hemangioma misdiagnosed as a schwannoma: A case report.The Journal of international medical research · 2025Article
- Clinical Significance of Somatic PIK3CA and MAP3K3 Mutations in Cerebral and Spinal Cavernous Malformations.Translational stroke research · 2025Article
- Reduction of neuronal activity mediated by blood-vessel regression in the adult brain.Nature communications · 2025Article
- Targeted Therapies for Slow-Flow Vascular Malformations.The Australasian journal of dermatology · 2025Review
- Case Report: Clinical and molecular features of a radiosensitive autoimmune polyendocrine syndrome type 1 patient with oral carcinoma.Frontiers in genetics · 2025Article
- Cerebral Cavernous Malformation: From Genetics to Pharmacotherapy.Brain and behavior · 2025Review
- Case Report: Single-cell RNA sequencing reveals cellular and molecular mechanisms in newborn cardiac hemangioma formation.Frontiers in cardiovascular medicine · 2025Article
- Review
- CRISPR/CasRx suppresses KRAS-induced brain arteriovenous malformation developed in postnatal brain endothelial cells in mice.JCI insight · 2024Article
Corrections and comments
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Authors and funding
26 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analysed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation [c.1323C>G (p.Ile441Met)] but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the CNS. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labelling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.
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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.