Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Xiaolei Xu¹  Kunli Jiao¹  Yonghe Ding¹  Jingchun Yang¹  Michael J. Ackerman²  Tong Lu³  HoN‐chi Lee³  David J. Tester³  John R. Giudicessi³  Yigang Li⁴  Kai Jiang⁵  Dao Wen Wang⁶  Peng Chen⁶  Dao Wu Wang⁷ 

[1] Department of Biochemistry and Molecular Biology Mayo Clinic Rochester MN;Department of Cardiovascular Medicine (Division of Heart Rhythm Services) Mayo Clinic Rochester MN;Department of Cardiovascular Medicine Mayo Clinic Rochester MN;Division of Cardiology Xinhua Hospital Shanghai Jiaotong University Shanghai China;Division of Nephrology and Hypertension Mayo Clinic Rochester MN;Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders Division of Cardiology Departments of Internal Medicine and Genetic Diagnosis Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China;State Key Laboratory of Reproductive Medicine Clinical Center of Reproductive Medicine and Department of Cardiology First Affiliated Hospital of Nanjing Medical University Nanjing China;

关键词: arrhythmogenic cardiomyopathy;    intercalated disc;    sorbin and SH3 domain‐containing 2;    susceptibility gene;   

DOI  :  10.1161/JAHA.119.017055

来源: DOAJ

【 摘 要 】

Background 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. Methods and Results 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. Conclusions 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.

【 授权许可】

Unknown