PUBLICATION
Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy
- Authors
- Ding, Y., Yang, J., Chen, P., Lu, T., Jiao, K., Tester, D.J., Giudicessi, J.R., Jiang, K., Ackerman, M.J., Li, Y., Wang, D.W., Lee, H.C., Wang, D.W., Xu, X.
- ID
- ZDB-PUB-200819-10
- Date
- 2020
- Source
- Journal of the American Heart Association 9(17): e017055 (Journal)
- Registered Authors
- Keywords
- arrhythmogenic cardiomyopathy, intercalated disc, sorbin and SH3 domain‐containing 2, susceptibility gene
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Adult
- Aged
- Animals
- Arrhythmias, Cardiac/genetics*
- Arrhythmias, Cardiac/physiopathology
- Arrhythmogenic Right Ventricular Dysplasia/genetics
- Arrhythmogenic Right Ventricular Dysplasia/physiopathology
- Cardiomyopathies/physiopathology*
- Case-Control Studies
- Disease Models, Animal
- Female
- Genetic Predisposition to Disease/genetics
- Humans
- Male
- Mice
- Mice, Knockout
- Middle Aged
- Mutation
- Myocardium/metabolism
- Myocardium/pathology*
- Phenotype
- RNA-Binding Proteins/genetics*
- PubMed
- 32808564 Full text @ J. Am. Heart Assoc.
Citation
Ding, Y., Yang, J., Chen, P., Lu, T., Jiao, K., Tester, D.J., Giudicessi, J.R., Jiang, K., Ackerman, M.J., Li, Y., Wang, D.W., Lee, H.C., Wang, D.W., Xu, X. (2020) Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy. Journal of the American Heart Association. 9(17):e017055.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping