气候变化领域集成服务门户(CCPortal): The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm

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DOI	10.1073/pnas.2018220118
	The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm
	Koopman C.D.; de Angelis J.; Iyer S.P.; Verkerk A.O.; Silva J.D.; Berecki G.; Jeanes A.; Baillie G.J.; Paterson S.; Uribe V.; Ehrlich O.V.; Robinson S.D.; Garric L.; Petrou S.; Simons C.; Vetter I.; Hogan B.M.; de Boer T.P.; Bakkers J.; Smith K.A.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	The establishment of cardiac function in the developing embryo is essential to ensure blood flow and, therefore, growth and survival of the animal. The molecular mechanisms controlling normal cardiac rhythm remain to be fully elucidated. From a forward genetic screen, we identified a unique mutant, grime, that displayed a specific cardiac arrhythmia phenotype. We show that loss-of-function mutations in tmem161b are responsible for the phenotype, identifying Tmem161b as a regulator of cardiac rhythm in zebrafish. To examine the evolutionary conservation of this function, we generated knockout mice for Tmem161b. Tmem161b knockout mice are neonatal lethal and cardiomyocytes exhibit arrhythmic calcium oscillations. Mechanistically, we find that Tmem161b is expressed at the cell membrane of excitable cells and live imaging shows it is required for action potential repolarization in the developing heart. Electrophysiology on isolated cardiomyocytes demonstrates that Tmem161b is essential to inhibit Ca2+ and K+ currents in cardiomyocytes. Importantly, Tmem161b haploinsufficiency leads to cardiac rhythm phenotypes, implicating it as a candidate gene in heritable cardiac arrhythmia. Overall, these data describe Tmem161b as a highly conserved regulator of cardiac rhythm that functions to modulate ion channel activity in zebrafish and mice. © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Arrhythmia; Cardiac; Forward genetics; Mouse; Zebrafish
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180490
作者单位	Department of Cardiac Development and Genetics, Hubrecht Institute, University Medical Centre Utrecht, Utrecht, 3584 CT, Netherlands; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center, Utrecht, 3584 CM, Netherlands; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Department of Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Medical Biology, Amsterdam University Medical Centre, Amsterdam, 1105 AZ, Netherlands; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia; Department of the Florey Institute, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics Theme, Murdoch Children's Research Institute, Parkville, VIC 3010, Australia; School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; Peter MacCallum Cancer Centre, The University of Melbourne, Parkville, VIC 3010, Australia
推荐引用方式 GB/T 7714	Koopman C.D.,de Angelis J.,Iyer S.P.,et al. The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm[J],2021,118(9).
APA	Koopman C.D..,de Angelis J..,Iyer S.P..,Verkerk A.O..,Silva J.D..,...&Smith K.A..(2021).The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Koopman C.D.,et al."The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).