The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm
| العنوان: | The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm |
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| المؤلفون: | Benjamin M. Hogan, Angela Jeanes, Steven Petrou, Geza Berecki, Laurence Garric, Ophelia V. Ehrlich, Irina Vetter, Cas Simons, Teun P. de Boer, Charlotte D. Koopman, Samuel D. Robinson, Swati Iyer, Veronica Uribe, Scott Paterson, Jason Da Silva, Arie O. Verkerk, Gregory J. Baillie, Jessica E. De Angelis, Jeroen Bakkers, Kelly A. Smith |
| المساهمون: | Hubrecht Institute for Developmental Biology and Stem Cell Research, Medical Biology, ACS - Amsterdam Cardiovascular Sciences |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America, 118(9). National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America, 118(9):e2018220118. National Academy of Sciences |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Periodicity, Embryo, Nonmammalian, Mouse, Forward genetics, Arrhythmias, Lethal, Animals, Genetically Modified, Mice, Myocyte, Developmental, Arrhythmias, Cardiac/genetics, Zebrafish, Conserved Sequence, Mice, Knockout, Nonmammalian, Multidisciplinary, biology, Gene Expression Regulation, Developmental, Heart Rate/genetics, Myocytes, Cardiac/metabolism, Cell biology, Embryo, Action Potentials/genetics, Cardiac/metabolism, Knockout mouse, Haploinsufficiency, Cardiac, Arrhythmia, Cardiac function curve, Calcium/metabolism, Knockout, Potassium/metabolism, Genetically Modified, Cardiac/genetics, Zebrafish Proteins/genetics, Animals, Membrane Proteins/genetics, Myocytes, Ion Transport, Base Sequence, Organogenesis/genetics, Animal, Mammalian, Cardiac arrhythmia, Embryo, Mammalian, biology.organism_classification, Disease Models, Animal, Gene Expression Regulation, Genes, Disease Models, Mutation, Genes, Lethal, Heart/embryology, Genetic screen |
| الوصف: | 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. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca136610721e5a7dc6a382d945333974Test https://doi.org/10.1073/pnas.2018220118Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ca136610721e5a7dc6a382d945333974 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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