The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm

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,...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (9), p.1-10
Main Authors: Koopman, Charlotte D., De Angelis, Jessica, Iyer, Swati P., Verkerk, Arie O., Da Silva, Jason, Berecki, Geza, Jeanes, Angela, Baillie, Gregory J., Paterson, Scott, Uribe, Veronica, Ehrlich, Ophelia V., Robinsonc, Samuel D., Garric, Laurence, Petrou, Steven, Simons, Cas, Vetter, Irina, Hogan, Benjamin M., de Boer, Teun P., Bakkers, Jeroen, Smith, Kelly A.
Format: Article
Language:English
Subjects:
Action potential
Arrhythmia
Biological Sciences
Blood flow
Calcium
Calcium currents
Calcium ions
Calcium signalling
Cardiac arrhythmia
Cardiomyocytes
Cell membranes
Channel gating
Danio rerio
Electrophysiology
Embryos
Evolutionary conservation
Genetic screening
Haploinsufficiency
Heart
Ion channels
Molecular modelling
Mutants
Mutation
Neonates
Phenotypes
Potassium currents
Rhythm
Zebrafish
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2018220118