Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene

Hong, Ying, Keylock, Annette, Jensen, Barbara, Jacques, Thomas S., Ogunbiyi, Olumide, Omoyinmi, Ebun, Saunders, Dawn, Mallick, Andrew A., Tooley, Madeleine, Newbury-Ecob, Ruth, Rankin, Julia, Williams, Hywel J. ORCID: https://orcid.org/0000-0001-7758-0312, Ganesan, Vijeya, Brogan, Paul A. and Eleftheriou, Despina 2020. Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene. Neurology Genetics 6 (4) , e448. 10.1212/NXG.0000000000000448

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Abstract

Objective 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	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.
Publisher:	Lippincott, Williams & Wilkins
ISSN:	2376-7839
Date of First Compliant Deposit:	29 July 2021
Date of Acceptance:	28 April 2020
Last Modified:	15 May 2023 01:47
URI:	https://orca.cardiff.ac.uk/id/eprint/142890

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