Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms
Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms
复制标题
DOI：
10.1016/j.jtcvs.2007.02.041
复制
发表时间：
2007-08-01
影响因子：
6
通讯作者：
Sundt, Thoralf M., III
中科院分区：
文献类型：
--
作者：
McKellar, Stephen H.;Tester, David J.;Sundt, Thoralf M., III
目的：二叶式主动脉瓣是一种常见疾病，与发生胸主动脉瘤和急性主动脉夹层的风险显著增加相关。然而，对患者发生胸主动脉瘤风险的预测是不准确的。我们假设，二叶式主动脉瓣患者的基因型变异有助于观察到的主动脉表型变异。因此，我们研究了最近报道的与二叶式主动脉瓣相关的NOTCH 1区域突变与接受手术修复的无关患者的二叶式主动脉瓣和胸主动脉瘤表型之间的潜在关系。我们使用基因组DNA对48名患有二叶主动脉瓣和胸主动脉瘤的无关受试者进行了NOTCH 1的靶向突变分析，变性高效液相色谱和DNA测序。我们集中在外显子中的突变与二叶式主动脉瓣已报告。将结果与三叶主动脉瓣对照组（n = 94）、二叶主动脉瓣对照组（n = 22）和正常胸主动脉瘤对照组（n = 28）进行比较。四个独特的，非同义在5例中鉴定出3种新的变异体（10.4%），而144例对照受试者中仅3例（2.1%）（P = 0.02）。其中，2个新的错义突变，A1343 V和P1390 T，观察到只有在患者二叶主动脉瓣和三叶主动脉aneurysm.Conclusions：这个有针对性的分析涉及NOTCH1外显子先前牵连在家族性和散发性二叶主动脉瓣表现出过度的NOTCH1错义变异的患者二叶主动脉瓣和胸主动脉瘤。识别易患主动脉瓣狭窄的易感基因可能会导致对二叶主动脉瓣患者的升主动脉进行基因导向的外科治疗。
Objectives: Bicuspid aortic valve is a common condition and is associated with a significantly increased risk of developing thoracic aortic aneurysms and acute aortic dissection. Patient-specific prediction of the risk of developing thoracic aortic aneurysm, however, is imprecise. We hypothesize that genotypic variations in patients with bicuspid aortic valves contribute to this observed variability in aortic phenotype. We, therefore, investigated the potential relationship between mutations in regions of NOTCH1 recently reported to be associated with bicuspid aortic valve and the phenotype of bicuspid aortic valve and thoracic aortic aneurysms in unrelated patients undergoing surgical repair.Methods: We performed a targeted mutational analysis of NOTCH1 using genomic DNA from 48 unrelated subjects with concomitant bicuspid aortic valve and thoracic aortic aneurysm using denaturing high-performance liquid chromatography and DNA sequencing. We focused on exons in which mutations associated with bicuspid aortic valve have been reported previously. Results were compared with control subjects with trileaflet aortic valves (n = 94), bicuspid aortic valves, and normal aortas ( n = 22) and in subjects with tricuspid aortic valves and thoracic aortic aneurysms ( n = 28).Results: Four unique, nonsynonymous ( 3 novel) variants were identified in 5 (10.4%) of 48 patients with concomitant bicuspid aortic valves and thoracic aortic aneurysms compared with only 3 (2.1%) of 144 control subjects (P = .02). Of these, 2 novel missense mutations, A1343V and P1390T, were observed only in patients with bicuspid aortic valves and tricuspid aortic aneurysms.Conclusions: This targeted analysis involving NOTCH1 exons previously implicated in familial and sporadic bicuspid aortic valve demonstrates overrepresentation of NOTCH1 missense variants among patients with bicuspid aortic valves and thoracic aortic aneurysms. Identification of aneurysm-predisposing susceptibility genes may lead to gene-directed surgical therapy of the ascending aorta for patients with bicuspid aortic valves.