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

Charlotte D Koopman, Jessica De Angelis, Swati P Iyer, Arie O Verkerk, Jason Da Silva, Geza Berecki, Angela Jeanes, Gregory J Baillie, Scott Paterson, Veronica Uribe, Ophelia V Ehrlich, Samuel D Robinson, Laurence Garric, Steven Petrou, Cas Simons, Irina Vetter, Benjamin M Hogan, Teun P de Boer, Jeroen Bakkers, Kelly A Smith

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number9
DOIs
Publication statusPublished - 02 Mar 2021

Keywords

  • Action Potentials/genetics
  • Animals
  • Animals, Genetically Modified
  • Arrhythmias, Cardiac/genetics
  • Base Sequence
  • Calcium/metabolism
  • Conserved Sequence
  • Disease Models, Animal
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • Genes, Lethal
  • Heart/embryology
  • Heart Rate/genetics
  • Ion Transport
  • Membrane Proteins/genetics
  • Mice
  • Mice, Knockout
  • Mutation
  • Myocytes, Cardiac/metabolism
  • Organogenesis/genetics
  • Periodicity
  • Potassium/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics

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