Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections
Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections
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DOI：
10.1016/j.ajhg.2013.06.019
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发表时间：
2013-08-08
影响因子：
9.8
通讯作者：
Milewicz, Dianna M.
中科院分区：
文献类型：
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作者：
Guo, Dong-Chuan;Regalado, Ellen;Milewicz, Dianna M.
导致血管平滑肌细胞（SMC）收缩减少的基因突变可导致遗传性胸主动脉瘤和夹层。对受胸主动脉疾病影响的远亲进行外显子组测序，随后对家族性胸主动脉疾病的其他先证者进行桑格测序，在4个家族中发现了相同的罕见变异，PRKG 1 c.530 G>A（p.Arg177 Gln）。在这些家族中，这种突变与主动脉疾病分离，合并的两点LOD评分为7.88。大多数受影响的个体（63%）在相对年轻的年龄（平均31岁，范围17-51岁）出现急性主动脉夹层。PRKG 1编码I型cGMP依赖性蛋白激酶（PKG-1），其在cGMP结合时被激活并控制SMC松弛。虽然p.Arg177G1n改变破坏了与调节结构域内高亲和力cGMP结合位点的结合，但改变的PKG-1即使在没有cGMP的情况下也是组成性活性的。PKG-1活性的增加导致成纤维细胞中肌球蛋白调节轻链磷酸化的减少，并被预测会导致血管SMC收缩减少。因此，PRKG 1功能获得性突变作为胸主动脉疾病的原因的鉴定提供了进一步的证据，表明适当的SMC收缩功能对于在整个生命周期中维持胸主动脉的完整性至关重要。
Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177G1n alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.