期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 4, 页码 1496-1508出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI98589
关键词
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资金
- Wellcome Trust [WT104076MA, WT098498]
- MRC [MRC_MC_UU_12012/5]
- Health Education East of England
- Wellcome Trust Translational Medicine and Therapeutics Programme
- MRC Human Genetics Unit Programme [MC_PC_U127585840]
- L'Oreal-Melanoma Research Alliance Team Award for Women in Science [401181]
- European Research Council [ZF-MEL-CHEMBIO-648489]
- Intramural Research Program of the National Human Genome Research Institute [HG200328 11, HG200388 03]
- UK National Institute for Health Research (Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust)
- UK National Institute for Health Research (Biomedical Research Centre at UCL)
- UK National Institute for Health Research (Biomedical Research Centre in Cambridge)
- UK National Institute for Health Research (Rare Disease Translational Research Collaboration)
- Wellcome Trust [104076/Z/14/Z] Funding Source: Wellcome Trust
- Great Ormond Street Hospital Childrens Charity [W1075F, W1075G, V1246] Funding Source: researchfish
- Medical Research Council [G120/875, MC_U127585840, MC_PC_U127585840, MC_UU_00007/9] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10046] Funding Source: researchfish
- The Brain Tumour Charity [GN-000382, GN-000359] Funding Source: researchfish
- Wellcome Trust [104076/Z/14/Z] Funding Source: researchfish
- MRC [MC_UU_00007/9, G120/875, MC_PC_U127585840, MC_U127585840, MC_UU_12012/5] Funding Source: UKRI
BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.
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