PRKAG2基因自发新突变K485E引起心脏电生理异常的机制研究

The PRKAG2 cardiac syndrome is a recently described, autosomal dominant genetic disease and caused by defects in the PRKAG2 gene which encodes the AMP-activated protein kinase (AMPK) γ2 regulatory subunit. Typically, affected patients present with myocardial hypertrophy and electrophysiological abnormalities. The current studies on PRKAG2 cardiac syndrome cannot explain the high incidence of arrhythmias. Previous evidence indicated that active AMPK may regulate the function of ion channels. Therefore, changes in basal AMPK activation due to PRKAG2 mutations may be arrhythmogenic by altering cardiac ion-channel function. In 2013, we reported a novel de novo PRKAG2 mutation (K485E) and the proband presented with serious clinical phenotypes, suggesting the mutation with strong pathogenicity. The purpose of this project is to investigate the mechanism of a novel PRKAG2 mutation associated with cardiac electrophysiological abnormalities. The study will be the first time to provide the direct evidence about a close relationship between PRKAG2 gene and cardiac ion channels, which might lead to important new mechanistic insights and potentially to new therapeutic opportunities for arrhythmias.

PRKAG2心脏综合征由编码一磷酸腺苷激活蛋白激酶（AMPK）γ2亚单位的PRKAG2基因突变所致。目前有关PRKAG2心脏综合征的研究无法解释其高发的心律失常发生率。据文献报道，活化的AMPK可调控离子通道的功能。由于PRKAG2基因编码的AMPK γ2亚单位通过调节α亚单位的活性而发挥作用，所以我们推测PRKAG2基因突变所致的AMPK活性改变可能通过影响心脏离子通道的功能而产生致心律失常作用。本项目以我们前期发现的PRKAG2基因自发的新突变K485E为基础，拟探讨该突变对AMPK基础活性、心肌细胞内糖原含量和心脏离子通道功能的影响及相关作用机制，以阐明PRKAG2基因自发的新突变K485E引起心脏电生理异常的病理生理过程，进一步明确PRKAG2心脏综合征的发病机制；同时将首次提供PRKAG2基因与心脏离子通道之间相互作用关系的直接证据，为研究心律失常的发生机制和治疗开辟新思路。

PRKAG2心脏综合征由编码一磷酸腺苷激活蛋白激酶（AMPK）γ2亚单位的PRKAG2基因突变所致。目前有关PRKAG2心脏综合征的研究无法解释其高发的心律失常发生率。据文献报道，活化的AMPK可调控离子通道的功能。由于PRKAG2基因编码的AMPK γ2亚单位通过调节α亚单位的活性而发挥作用，所以我们推测PRKAG2基因突变所致的AMPK活性改变可能通过影响心脏离子通道的功能而产生致心律失常作用。本项目以我们前期发现的PRKAG2基因自发的新突变K485E为基础，拟探讨该突变对AMPK基础活性、心肌细胞内糖原含量和心脏离子通道功能的影响及相关作用机制，以阐明PRKAG2基因自发的新突变K485E引起心脏电生理异常的病理生理过程。先证者在课题期间因为进行性加重的心衰接受了心脏移植治疗，对其进行研究发现，移植的心脏组织可见显著的细胞内空泡形成，糖原内容增加和肌原纤维丢失，以右房和左室最为明显。没有观察到肌纤维排列紊乱，仅仅有少量的纤维化。与对照的心肌相比，右房AMPK活性显著减低。左右心房钾通道Kir6.2，Kir2.1和Kv1.5的免疫荧光信号均显著减少；钾通道Kv4.3，Kv11.1，Kv7.1和钙通道Cav1.2信号在右房表达显著降低，左房仅轻微减少或不变；左右心房钠通道Nav1.5的免疫荧光信号均无显著改变。 居于这些发现提示，PRKAG2心脏综合征心肌病理呈非均质性改变，这与临床型一致。在终末期，AMPK活性显著减低，心肌离子通道蛋白的表达改变显著。