PUBLICATION

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

Authors
Koopman, C.D., De Angelis, J., Iyer, S.P., Verkerk, A.O., Da Silva, J., Berecki, G., Jeanes, A., Baillie, G.J., Paterson, S., Uribe, V., Ehrlich, O.V., Robinson, S.D., Garric, L., Petrou, S., Simons, C., Vetter, I., Hogan, B.M., de Boer, T.P., Bakkers, J., Smith, K.A.
ID
ZDB-PUB-210220-2
Date
2021
Source
Proceedings of the National Academy of Sciences of the United States of America   118(9): (Journal)
Registered Authors
Bakkers, Jeroen, Da Silva, Jason, Hogan, Ben M., Smith, Kelly
Keywords
arrhythmia, cardiac, forward genetics, mouse, zebrafish
MeSH Terms
  • Organogenesis/genetics
  • Arrhythmias, Cardiac/genetics*
  • Arrhythmias, Cardiac/metabolism
  • Arrhythmias, Cardiac/pathology
  • Ion Transport
  • Heart/embryology
  • Heart/physiopathology
  • Calcium/metabolism
  • Heart Rate/genetics*
  • Gene Expression Regulation, Developmental
  • Mice
  • Conserved Sequence
  • Action Potentials/genetics
  • Genes, Lethal
  • Membrane Proteins/deficiency
  • Membrane Proteins/genetics*
  • Disease Models, Animal
  • Animals
  • Mutation*
  • Potassium/metabolism
  • Embryo, Nonmammalian
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
  • Mice, Knockout
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Embryo, Mammalian
  • Periodicity
  • Base Sequence
  • Zebrafish
  • Animals, Genetically Modified
(all 31)
PubMed
33597309 Full text @ Proc. Natl. Acad. Sci. USA
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
tmem161buq4ks/+standard conditionsAdult
tmem161buq4ks/+standard conditionsAdult
tmem161buq4ks/+standard conditionsAdult
tmem161buq4ks/+; tmem161buq5ks/+standard conditionsLong-pec
tmem161buq4ks/uq4ksstandard conditionsProtruding-mouth
tmem161buq4ks/uq4ksstandard conditionsDay 5
tmem161buq4ks/uq4ksstandard conditionsDay 5
tmem161buq4ks/uq4ksstandard conditionsDays 14-20
tmem161buq4ks/uq4ks; ccu1Tg; hu6531Tgstandard conditionsProtruding-mouth
tmem161buq4ks/uq4ks; ccu1Tg; hu6531Tgstandard conditionsProtruding-mouth
1 - 10 of 15
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bns7TgTransgenic Insertion
    ccu1TgTransgenic Insertion
      f2TgTransgenic Insertion
        hu6531TgTransgenic Insertion
          hu11688TgTransgenic Insertion
            uq4ks
              		Point Mutation
              uq5ks
                		Indel
                uq24ksTgTransgenic Insertion
                  y7TgTransgenic Insertion
                    1 - 9 of 9
                    Show
                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    tmem161bCRISPR1-tmem161bCRISPR
                    tnnt2aMO1-tnnt2aMRPHLNO
                    1 - 2 of 2
                    Show
                    Fish
                    Fish
                    bns7Tg; uq24ksTg
                    tmem161buq4ks/+
                    tmem161buq4ks/+; tmem161buq5ks/+
                    tmem161buq4ks/uq4ks
                    tmem161buq4ks/uq4ks; ccu1Tg; hu6531Tg
                    tmem161buq4ks/uq4ks; hu11688Tg
                    uq24ksTg
                    1 - 7 of 7
                    Show
                    Antibodies
                    No data available
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    CitrineEFGCitrine
                    DsRed2EFGDsRed2
                    EGFPEFGEGFP
                    GAL4FFEFGGAL4FF
                    GCaMPEFGGCaMP
                    mCherryEFGmCherry
                    VSFPEFGVSFP
                    1 - 7 of 7
                    Show
                    Mapping
                    No data available
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                    Citation
                    Koopman, C.D., De Angelis, J., Iyer, S.P., Verkerk, A.O., Da Silva, J., Berecki, G., Jeanes, A., Baillie, G.J., Paterson, S., Uribe, V., Ehrlich, O.V., Robinson, S.D., Garric, L., Petrou, S., Simons, C., Vetter, I., Hogan, B.M., de Boer, T.P., Bakkers, J., Smith, K.A. (2021) The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm. Proceedings of the National Academy of Sciences of the United States of America. 118(9):.