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dc.contributor.authorRankin, Julia
dc.date.accessioned2020-11-24T13:55:48Z
dc.date.available2020-11-24T13:55:48Z
dc.date.issued2020-06-10
dc.identifier.citationHong Y et al. Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene. Neurol Genet. 2020 Jun 10;6(4):e448.en_US
dc.identifier.pmid32637631
dc.identifier.doi10.1212/NXG.0000000000000448
dc.identifier.urihttps://rde.dspace-express.com/handle/11287/621573
dc.description.abstractObjective: To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma (CBL) gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast proliferation and migration and enhanced angiogenesis and collateral vessel formation. Methods: We performed whole-exome sequencing in 11 separate families referred to Great Ormond Street Hospital, London, with suspected genetic cause for clinical presentation with severe progressive cerebral arteriopathy. Results: We identified heterozygous variants in the CBL gene in 5 affected cases from 3 families. We show that impaired CBL-mediated degradation of cell surface tyrosine kinase receptors and dysregulated intracellular signaling through the RAS-MAPK pathway contribute to the pathogenesis of the observed arteriopathy. Mutated CBL failed to control the angiogenic signal relay of vascular endothelial growth factor receptor 2, leading to prolonged tyrosine kinase signaling, thus driving angiogenesis and collateral vessel formation. Mutant Cbl promoted myofibroblast migration and proliferation contributing to vascular occlusive disease; these effects were abrogated following treatment with a RAF-RAS-MAPK pathway inhibitor. Conclusions: We provide a possible mechanism for the arteriopathy associated with heterozygous CBL variants. Identification of the key role for the RAS-MAPK pathway in CBL-mediated cerebral arteriopathy could facilitate identification of novel or repurposed druggable targets for treating these patients and may also provide therapeutic clues for other cerebral arteriopathies.en_US
dc.language.isoenen_US
dc.publisherWolters Kluwer Health, Inc.en_US
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32637631/en_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.en_US
dc.rightsCC0 1.0 Universal*
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/*
dc.subjectWessex Classification Subject Headings::Neurologyen_US
dc.subjectCerebral arteriopathyen_US
dc.subjectheterozygous variantsen_US
dc.titleCerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma geneen_US
dc.typeJournal Articleen_US
dc.identifier.journalNeurology. Genetics.en_US
dc.identifier.pmcidPMC7323481
dc.description.noteThis article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.en_US
dc.description.fundingY. Hong was supported for this work by Versus Arthritis (grant 21791) and Rosetrees Trust (grant A1700). D. Eleftheriou was supported by Versus Arthritis (grants 20164 and 21593). A. Keylock was supported by a BHF PhD studentship. B. Jensen is supported by a GOSH Children’s Charity grant (CP_RSRCH_003). P.A. Brogan and D. Eleftheriou also acknowledge support from Great Ormond Street Hospital Children’s Charity. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.en_US
dc.type.versionPublisheden_US
dc.description.admin-noteaccepted version (12 month embargo)en_US


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This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Except where otherwise noted, this item's license is described as This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.