A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene
Year: 2022
Type: article
Abstract: Sick sinus syndrome (SSS) is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. Here, we aim to develop a phenotype-based forward genetic approach in the zebrafish ( Danio rerio ) animal model for discovering essential genes which dysfunction could result in SSS-like phenotypes. Previously we showed the generation of protein trap library by using a revertible gene-breaking transposon (GBT)-based insertional mutagenesis system. Here, we reported the generation of a collection of 35 zebrafish insertional cardiac lines derived from this protein trap library, which was screened using electrocardiographic measurements. As a result, three mutants with SSS-like phenotypes were identified. We then focused on one of these 3 GBT mutants called GBT411 in which dnajb6b gene was disrupted, and conducted expressional, genetic, transcriptome, and electrophysiological studies using both zebrafish and mouse models. These studies confirmed the identity of Dnajb6 as a novel SSS causative gene with a unique expression pattern within the specialized population of sinus node pacemaker cardiomyocytes that lack the expression of HCN4 channels. Together, this study demonstrates the feasibility of a genetic screening approach in an adult vertebrate animal model for discovering new genetic factors for a heart rhythm disorder such as SSS.
Source: eLife
DOI: 10.7554/elife.77327
Institutions: Qingdao University, Mayo Clinic, Affiliated Hospital of Qingdao University, University of Wisconsin–Madison, University of California, San Francisco, Shanghai Jiao Tong University, XinHua Hospital, Central South University, Xiangya Hospital Central South University, Jiading District Central Hospital, Shanghai University of Medicine and Health Sciences, University of California, Davis, University of California, Irvine, University of Maryland, Baltimore, The University of Texas Health Science Center at Houston
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Supraventricular Arrhythmogenesis associated with CPVT-linked RyR mutations, Cloud-based High-throughput Acquisition and Analytics of Zebrafish Electrocardiogram for Cardiac Studies and Drug Development, The role of compartmentalized regulation of calcium signalling in atrial remodelling in heart failure, Cross-talk of Ca, CaMKII, and beta-adrenergic signaling in atrial fibrillation, G4540039748, The role of caveolin-3 in the mouse sino-atiral node functioning and atrail arrhythmogenesis, Development of the Predictive NeuroCardiovascular Simulator, Modeling of subcellular signaling crosstalk in failing myocytes, G7280553491, Systematic Vertebrate Functional Genomics, Sex differences in atrial electrophysiology and antiarrhythmic drug responses: a combined modeling and experiments study, G9000097116, Systematic Vertebrate Functional Genomics, Genetic dissection of Cardiac Conduction System homeostasis and Repair, Multiscale Systems to Elucidate Susceptibility and Cardioprotective Mechanisms in Cardio-oncology, Sex-specific arrhythmogenic mechanisms of atrial fibrillation, Epicardial remodeling in cardiomyopathy and cardiac aging, Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling
OpenAlex ID: W4306698769