Back to Search
Start Over
The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 02; Vol. 118 (9). - Publication Year :
- 2021
-
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 Ca <superscript>2+</superscript> and K <superscript>+</superscript> 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.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Action Potentials genetics
Animals
Animals, Genetically Modified
Arrhythmias, Cardiac metabolism
Arrhythmias, Cardiac pathology
Base Sequence
Calcium metabolism
Conserved Sequence
Disease Models, Animal
Embryo, Mammalian
Embryo, Nonmammalian
Gene Expression Regulation, Developmental
Genes, Lethal
Heart embryology
Heart physiopathology
Ion Transport
Membrane Proteins genetics
Mice
Mice, Knockout
Myocytes, Cardiac pathology
Organogenesis genetics
Periodicity
Potassium metabolism
Zebrafish
Zebrafish Proteins genetics
Arrhythmias, Cardiac genetics
Heart Rate genetics
Membrane Proteins physiology
Mutation
Myocytes, Cardiac metabolism
Zebrafish Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33597309
- Full Text :
- https://doi.org/10.1073/pnas.2018220118