Aim Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor β (TGF-β)-signaling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-β maturation. Methods and results Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection. FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-β processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-β-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibers were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-β signaling variably, indicating effect modification by individual genetic backgrounds. Conclusion FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-β signaling, depending on individual genetic backgrounds.

中文翻译：

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前蛋白转化酶 FURIN 是一种损害 TGF-β 信号传导的新型动脉瘤易感基因

目的 主动脉瘤 (AA) 经常涉及主动脉中转化生长因子 β (TGF-β) 信号传导的失调。在此，鉴于 FURIN 在前 TGF-β 成熟中作为前蛋白转化酶的作用，FURIN 被测试为动脉瘤易感基因。方法和结果 通过对 781 名无关的主动脉瘤患者和受影响的亲属进行全外显子组测序，检测到罕见的 FURIN 变异。 13 种罕见的杂合性 FURIN 变异发生在 3.7%（29 名）不相关的指数 AA 患者中，其中 72% 患有多发性动脉瘤或夹层。这些变体的 FURIN 成熟和活性在体外降低。患者来源的成纤维细胞显示出前 TGF-β 加工、下游效应器 SMAD2 和激酶 ERK1/2 的磷酸化以及 TGF-β 反应性 ACTA2 基因的稳态 mRNA 水平降低。在主动脉组织中，胶原蛋白和原纤维蛋白纤维受到影响。在 10 个不相关的病例中观察到的一种变异 (R745Q) 对 TGF-β 信号传导产生不同程度的影响，表明个体遗传背景对效应的影响。结论 FURIN 是老年患者腹部、胸部和多发主动脉或中型动脉瘤的一种新的、常见的遗传倾向，其影响细胞内 TGF-β 信号传导，具体取决于个体遗传背景。