A Functional Assay for Sick Sinus Syndrome Genetic Variants.

Autor:	Jou CJ; Division of Pediatric Cardiology, Cleveland Clinic, Cleveland, Utah, USA., Arrington CB; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Barnett S; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Shen J; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA., Cho S; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Sheng X; Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., McCullagh PC; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Bowles NE; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Pribble CM; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Saarel EV; Division of Pediatric Cardiology, Cleveland Clinic, Cleveland, Utah, USA., Pilcher TA; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Etheridge SP; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA., Tristani-Firouzi M; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA.; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, USA.
Jazyk:	angličtina
Zdroj:	Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology [Cell Physiol Biochem] 2017; Vol. 42 (5), pp. 2021-2029. Date of Electronic Publication: 2017 Aug 11.
DOI:	10.1159/000479897
Abstrakt:	Background/aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. (© 2017 The Author(s). Published by S. Karger AG, Basel.)
Databáze:	MEDLINE
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