心房病变是房性心律失常和致死致残性卒中的重要病因，机制不明。. 我们发现一个临床表现为心房病变的家系，基因检测示核纤层蛋白基因移码突变。该蛋白为核膜重要结构蛋白，与染色质核纤层相关结构域结合调控基因组表达。前期我们构建了基因编辑小鼠，验证了心房表型，并发现其：1.心房肌染色质开放性改变，E3泛素连接酶（Siah-1）基因↑且其与核纤层蛋白相互作用；2.HIPK2↓且其与Siah-1相互作用。近期研究表明HIPK2↓通过抑制ERK通路诱发心肌细胞凋亡。. 本实验拟探究该突变中：1.心房肌核纤层相关结构域染色质开放程度及基因表达谱；2.Siah-1↑诱导心房肌细胞凋亡致心房病变的作用；3.Siah-1↑是否通过降解HIPK2抑制ERK通路进而诱导心房肌细胞凋亡致心房病变。旨在揭示该突变中Siah-1基因↑致心房病变机制，为遗传性心房病变机制及治疗研究提供新思路。

Atrial lesion is an important cause of atrial arrhythmias and fatal and disabled stroke, and its pathogenesis is still unclear..We found a family with clinical manifestation of atrial lesions, and detected as a lamin gene frameshift mutation. Lamin is an important structural protein of nuclear membrane, which binds to lamin associated domains of chromatin to regulate gene expression. In the early stage, we constructed corresponding gene-edited mice and verified the atrial phenotype. In the gene-edited mice, we found that: 1. The chromatin opening of atrial muscle was significantly changed. E3 ubiquitin ligase (Siah-1) gene expression was increased and it interacted with lamin; 2. The level of HIPK2 protein was decreased and it interacted with Siah-1. A recent study showed that decreased HIPK2 level could induce the apoptosis of cardiomyocytes through ERK pathway inhibition..The aim of this study is to investigate: 1. The opening degree of lamin associated domains related chromatin and gene expression profile in atrial myocytes; 2. The effect of Siah-1 on inducing apoptosis of atrial myocytes and causing atrial lesions; 3. Whether the increased Siah-1 level could induce atrial myocytes apoptosis through degradation of HIPK2 and subsequent ERK pathway inhibition. The aim of this study is to reveal the mechanism of atrial lesions induced by Siah-1 gene up-regulation in this mutation, and to provide new ideas for investigating mechanisms and therapeutic targets in hereditary atrial lesions.