Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy.
Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy.
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DOI：
10.1161/jaha.119.017055
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发表时间：
2020-09
影响因子：
5.4
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Ding Y;Yang J;Chen P;Lu T;Jiao K;Tester DJ;Giudicessi JR;Jiang K;Ackerman MJ;Li Y;Wang DW;Lee HC;Wang DW;Xu X
Sorbs2b （sorbin and SH3 domain‐containing 2b）最近在斑马鱼突变筛选中被鉴定为一种心肌病基因。然而，其哺乳动物同类的心脏功能仍然难以捉摸。我们对Sorbs2同源基因在小鼠中的表达和亚细胞定位进行了详细的分析，并对Sorbs2敲除小鼠进行了表型表征。Sorbs2在小鼠心脏中高度表达，并编码一种主要定位于嵌入盘的粘附连接/桥粒蛋白。小鼠中Sorbs2蛋白几乎完全缺失的突变导致人类心律失常性心肌病（ACM）的表型特征，包括右心室扩张、右心室功能障碍、自发性室性心动过速和过早死亡。Sorbs2是维持插入椎间盘结构完整性所必需的。它的缺失导致了严重的心脏电重构，并伴有脉冲传导受损和动作电位紊乱。人类ACM患者的靶向测序发现，在59例ACM患者队列中，有2例与ACM无关的个体中发现了2种罕见的剪接变异，被归类为可能致病。Sorbs2基因敲除小鼠表现出与人类ACM相似的几个关键特征。虽然初步的人类遗传学研究支持SORBS2作为新的ACM易感基因的候选资格，但未来需要在更大的ACM队列中进行验证。
Sorbs2b (sorbin and SH3 domain‐containing 2b) was recently identified as a cardiomyopathy gene from a zebrafish mutagenesis screen. However, cardiac functions of its mammalian ortholog remain elusive. We conducted a detailed expression and subcellular localization analysis of Sorbs2 ortholog in mice and a phenotypic characterization in Sorbs2 knockout mice. Sorbs2 is highly expressed in the mouse heart and encodes an adhesion junction/desmosome protein that is mainly localized to the intercalated disc. A mutation with near complete depletion of the Sorbs2 protein in mice results in phenotypes characteristic of human arrhythmogenic cardiomyopathy (ACM), including right ventricular dilation, right ventricular dysfunction, spontaneous ventricular tachycardia, and premature death. Sorbs2 is required to maintain the structural integrity of intercalated disc. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Targeted sequencing of human patients with ACM identified 2 rare splicing variants classified as likely pathogenic were in 2 unrelated individuals with ACM from a cohort of 59 patients with ACM. The Sorbs2 knockout mouse manifests several key features reminiscent of human ACM. Although the candidacy of SORBS2 as a new ACM‐susceptibility gene is supported by preliminary human genetics study, future validation in larger cohorts with ACM is needed.