Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections
Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections
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DOI：
10.1007/s00109-012-0931-y
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发表时间：
2013-01-01
影响因子：
4.7
通讯作者：
Tian, Xiao-Li
中科院分区：
文献类型：
--
作者：
Wang, Wen-Jing;Han, Peili;Tian, Xiao-Li
已知转化生长因子β信号通路的过度激活和由基因突变引起的细胞骨架紊乱是导致遗传性胸主动脉瘤和夹层（TAAD）的原因，TAAD是一种危及生命的血管疾病。为了研究基因型-表型的相关性，我们在7个受影响的家族和22个散发患者中筛选了TAAD的转录因子1（FBN 1）、转化生长因子β受体1（TGFBR 1）和转化生长因子β受体2（TGFBR 2）的基因突变。在FBN 1中发现的19个潜在突变中，11个是新的，而其他的是复发性的。在TGFBR 2中检测到两个突变。8名患者在这些基因中没有任何突变。在转染的HEK 293细胞中FBN 1 c.5917+ 6 T> C的表征表明，它引起外显子47的跳跃，导致与马凡氏综合征相关的第33个钙结合表皮生长因子样结构域的丢失。与外显子46相比，所有携带者中47的跳读均未引起晶状体异位。为了将不同人类祖先的基因型与表型相关联，我们回顾了已发表的FBN 1突变研究，发现中国人中提前终止密码子或剪接突变的患者发生心血管缺陷的概率显著高于错义突变的患者（91.7% vs 54.2%，P = 0.0307）或非半胱氨酸相关点突变组（88.9% vs 33.3%，P = 0.0131）。因此，我们得出结论，FBN 1的外显子47跳读优先导致心血管缺陷，人类祖先影响TAAD的基因型-表型相关性。
Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-beta receptor-1 (TGFBR1) and transforming growth factor-beta receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T > C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.