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.

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.

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.

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.

报告一系列与 casitas B 系淋巴瘤 ( CBL ) 基因杂合变异相关的脑动脉病患者，并检查已鉴定的突变 Cbl 蛋白的功能作用。我们假设突变的 Cbl 不能作为 RAS-丝裂原活化蛋白激酶 (MAPK) 信号通路的负调节因子，导致血管成纤维细胞增殖和迁移增强，血管生成和侧支血管形成增强。

我们对转诊至伦敦大奥蒙德街医院的 11 个独立家庭进行了全外显子组测序，这些家庭怀疑遗传原因导致严重进行性脑动脉病的临床表现。

我们在来自 3 个家庭的 5 个受影响病例中鉴定了CBL基因中的杂合变体。我们表明，受损的CBL介导的细胞表面酪氨酸激酶受体降解和通过 RAS-MAPK 途径失调的细胞内信号传导有助于观察到的动脉病的发病机制。突变的CBL未能控制血管内皮生长因子受体 2 的血管生成信号中继，导致酪氨酸激酶信号延长，从而驱动血管生成和侧支血管形成。突变体 Cbl 促进肌成纤维细胞迁移和增殖，导致血管闭塞性疾病；这些影响在用 RAF-RAS-MAPK 通路抑制剂治疗后被消除。

我们为与杂合CBL变体相关的动脉病提供了一种可能的机制。确定 RAS-MAPK 通路在CBL介导的脑动脉病中的关键作用有助于确定用于治疗这些患者的新的或重新利用的药物靶点，也可能为其他脑动脉病提供治疗线索。