ObjectivesIntracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian‐specific NOTCH3 p.R75P mutation.MethodsThis retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi‐Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations.ResultsAmong 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45–37.31), multiple CMB (3.00, 1.34–6.71), and absence of temporopolar lesions (4.91, 2.29–10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83–35.89), multiple CMB (1.90, 1.01–3.56), and absence of temporopolar lesions (2.32, 1.08–4.97). Structural analysis revealed solvent‐exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations.InterpretationNOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024

中文翻译：

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伴有低血管 NOTCH3 聚集特性的 NOTCH3 p.R75P 突变相关的伴有皮质下梗死和白质脑病的促出血性常染色体显性遗传性脑动脉病

目的 伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病中的脑内出血 (ICH) 和脑微出血 (CMB) 在东亚人群中比在欧洲白人血统中更常见。我们假设种族差异可以用东亚特有的文化来解释缺口3p.R75P 突变。方法这项回顾性观察性研究纳入了日本和韩国队列中的 118 名患有常染色体显性遗传性脑动脉病并伴有皮质下梗死和白质脑病的患者。我们使用准泊松回归模型研究了 p.R75P 突变是否与症状性 ICH 和多发 CMB (>5) 相关。我们通过计算机预测了 NOTCH3 胞外域蛋白结构，并对一些患者的皮肤血管进行了分级的 NOTCH3 胞外域免疫染色，随后对 p.R75P 和其他常规突变进行了比较。 结果 在 63 名日本患者中（中位年龄 55 岁；56% 为男性）， 15 名患者存在 p.R75P 突变，与症状性 ICH（调整后相对风险 9.56，95% CI 2.45–37.31）、多发 CMB（3.00，1.34–6.71）以及术后无颞极病变（4.91，2.29–10.52）显着相关。调整年龄、性别、高血压和抗血栓药物。在韩国队列中（n = 55；中位年龄 55 岁；51% 为男性），p.R75P 突变 (n = 13) 也与症状性 ICH (8.11, 1.83–35.89)、多发性 CMB (1.90, 1.01– 3.56），并且没有颞极病变（2.32，1.08-4.97）。结构分析显示，常规突变中存在溶剂暴露的游离半胱氨酸硫醇，直接导致聚集，而 p.R75P 中立体化学不相容的脯氨酸残基结构降低了正确的二硫键形成概率，间接导致聚集。病理学上，p.R75P突变导致血管NOTCH3胞外域积累比其他常规突变更少。缺口3p.R75P 突变与出血表现、较轻的颞极病变和独特的突变蛋白结构特性相关。安神经学 2024