1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [3].
1] Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3].
Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.
Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
心肌梗死是西方世界的主要死因，通常发生在冠状动脉中动脉粥样硬化斑块上的纤维帽破裂时。由此导致的血液暴露于动脉粥样硬化物质，随后触发血栓形成，从而阻塞动脉。阳性家族史对冠状动脉疾病和心肌梗死的遗传易感性的预测价值最好地证明了这一点。在有多个受影响个体的家族中进行下一代测序，彻底改变了突变识别。在这里，我们报告了两个功能相关基因 GUCY1A3（p.Leu163Phefs*24）和 CCT7（p.Ser525Leu）中的两个私有杂合突变在一个扩展的心肌梗死家族中的分离。GUCY1A3 编码可溶性鸟苷酸环化酶（α1-sGC）的α1 亚基，CCT7 编码 CCTη，一种无尾复合物多肽 1 环复合物的成员，除其他功能外，它还稳定可溶性鸟苷酸环化酶。一氧化氮刺激后，可溶性鸟苷酸环化酶生成 cGMP，诱导血管舒张并抑制血小板活化。我们在体外证明，GUCY1A3 和 CCT7 中的突变均严重降低了α1-sGC 和β1-sGC 蛋白含量，并损害了可溶性鸟苷酸环化酶活性。此外，二基因突变携带者的血小板中可溶性鸟苷酸环化酶蛋白含量减少，因此显示出减少的一氧化氮诱导的 cGMP 形成。缺乏α1-sGC 蛋白的小鼠在局部创伤后微循环中血栓形成加速。从一个严重受影响的家庭开始，我们已经确定了可溶性鸟苷酸环化酶依赖性一氧化氮信号传导受损与心肌梗死风险之间的联系，可能是通过加速血栓形成。纠正这种缺陷可能为降低心肌梗死风险提供新的治疗靶点。
