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

Abstract

ObjectiveTo 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

“…Recent emerging evidence also suggests a critical role of CBL in angiogenesis and endothelial cells signaling [ 16 ]. Defective CBL function seems to promote myofibroblast migration into the endothelium and subsequent proliferation via signaling elicited by the PDGF receptor, potentially contributing to the vascular disorders [ 46 ]. It is therefore reasonable that CBL mutations contribute to endothelial damage even if the underpinning of the biological mechanisms needs to be fully uncovered.…”

Role of CBL Mutations in Cancer and Non-Malignant Phenotype

“…Other reports later described vasculopathies primarily affecting cerebral blood vessels, such as moyamoya disease in patients with germline CBL mutations [37,67]. Recently, heterozygous somatic CBL mutations have also been reported in patients with cerebral arteriopathy of unknown origin [68,69]. Moyamoya disease is a cerebral vasculopathy characterized by a progressive stenosis of the terminal internal carotid arteries with subsequent development of abnormal collateral vessels, leading to ischemic and hemorrhagic stroke in both children and adults.…”