The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm
Koopman, Charlotte D.; de Angelis, Jessica; Iyer, Swati P.; Verkerk, Arie O.; Silva, Jason Da; Berecki, Geza; Jeanes, Angela; Baillie, Gregory J.; Paterson, Scott; Uribe, Veronica; Ehrlich, Ophelia V.; Robinson, Samuel D.; Garric, Laurence; Petrou, Steven; Simons, Cas; Vetter, Irina; Hogan, Benjamin M.; de Boer, Teun P.; Bakkers, Jeroen; Smith, Kelly A.
(2021) Proceedings of the National Academy of Sciences of the United States of America, volume 118, issue 9, pp. 1 - 10
(Article)
Abstract
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
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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.
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Keywords: Arrhythmia, Cardiac, Forward genetics, Mouse, Zebrafish, mouse, arrhythmia, zebrafish, forward genetics, cardiac, General, Journal Article
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. This work was supported by research grants from the Australian Research Council and the National Health and Medical Research Council of Australia. Confocal microscopy was performed at the Australian Cancer Research Foundation Dynamic Imaging Centre for Cancer Biology and the Biological Optical Microscopy Platform, with image analysis guidance from Ellie Cho and Shane Cheung. We also acknowledge the support from The Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centres, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT). We thank Y. Onderwater and B. de Jonge for technical assistance and R. Teasdale and J. Vandenberg for helpful discussions. The Tmem161bLacZ/+ mouse strain used in this research was generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (http://www.komp.org/). NIH grants to Velocigene at Regeneron Pharaceuticals, Inc. (U01HG004085), and the CSD Consortium (U01HG004080) funded the generation of gene-targeted embryonic stem cells for 8,500 genes in the KOMP program and archived and distributed by the KOMP repository at the University of California, Davis. The Alcama antibody (zn‐8) was obtained from the Developmental Studies Hybridoma Bank, created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH and maintained at the University of Iowa. Funding Information: This work was supported by research grants from the Australian Research Council and the National Health and Medical Research Council of Australia. Confocal microscopy was performed at the Australian Cancer Research Foundation Dynamic Imaging Centre for Cancer Biology and the Biological Optical Microscopy Platform, with image analysis guidance from Ellie Cho and Shane Cheung. We also acknowledge the support from The Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centres, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT). We thank Y. Onderwater and B. de Jonge for technical assistance and R. Teasdale and J. Vandenberg for helpful discussions. The Tmem161bLacZ/+ mouse strain used in this research was generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (http://www.komp.org/). NIH grants to Velocigene at Regeneron Pharaceuticals, Inc. (U01HG004085), and the CSD Consortium (U01HG004080) funded the generation of gene-targeted embryonic stem cells for 8,500 genes in the KOMP program and archived and distributed by the KOMP repository at the University of California, Davis. The Alcama antibody (zn?8) was obtained from the Developmental Studies Hybridoma Bank, created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH and maintained at the University of Iowa. Publisher Copyright: © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
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