锚蛋白（AnkB）基因突变与多种心律失常相关，但其具体致病分子机制尚不清楚。AnkB的C末端是突变好发区域，然而该区域突变位点的在体功能分析以及相关分子机制报道罕见。我们前期研究结果发现 AnkB基因C末端突变E1799K，构建了AnkB-E1799K杂合突变敲入小鼠（AnkB+/E1799K）并诱发出室速表型，在AnkB+/E1799K鼠心脏组织中检测到钙离子通道调控蛋白IP3R的表达升高。因此我们提出假设：C末端突变E1799K是否通过IP3R引起心肌细胞电紊乱导致心律失常。本课题将在已构建的AnkB+/E1799K小鼠、离体心肌细胞、HEK293细胞水平上，采用细胞电生理技术（钙火花；钙瞬变等）、分子遗传、蛋白表达和相互作用等分子生物学技术来探讨AnkB的C末端突变通过IP3R触发心肌电紊乱致心律失常的分子机制。该研究将为室速机制解析提供新的分子遗传学理论基础及潜在的干预靶点。

Mutations in the ankyrin (AnkB) gene have been found to be associated with a variety of arrhythmias, but the molecular mechanisms underlying their pathogenesis are unclear. The C-terminal of AnkB is a mutation-prone region, but the in vivo functional analysis and related molecular mechanisms from C terminal mutations have not been reported. Our preliminary study found that the ANK2 variant (p.E1799K) localized to the C-terminal, and we generated knock-in (KI) mice carrying the p.E1799K variant. Immunoblots revealed that the calcium regulation channel IP3R was significantly increased in the KI mice hearts. Therefore, we hypothesized that whether the C-terminal mutation E1799K causes myocardial cell electrical disturbance through IP3R leads to arrhythmia. This study intends to use mouse cardiomyocytes and KI mice models, using cell electrophysiological techniques (action potential; calcium spark; calcium transients ;etc), protein expression and interaction techniques to explore the molecular mechanism of C-terminal AnkB mutations triggering arrhythmias induced by myocardial electrical disturbances. This study will provide a new theoretical basis for molecular genetics and a potential target of treatment for arrhythmia electrical disturbance.