Researchers from the groups of Jeroen Bakkers (Hubrecht Institute/UMC Utrecht), Teun de Boer (UMC Utrecht) and Kelly Smith (University of Melbourne) discovered that a still very unknown gene called Tmem161b plays an important role in the regulation of the heart rhythm. Mutations in this gene disrupt the electrical impulses that run through the heart – so-called action potentials – in zebrafish and mice. The shape and frequency of these action potentials determine the heart rhythm. The researchers hope that, in the long-term, their findings can contribute to better diagnosis and treatment of cardiac arrythmias in humans. The study was published in the prestigious scientific journal PNAS on the 15th of February.
In the case of a cardiac arrythmia, the heart beats too fast, too slowly or irregularly. In severe cases, the blood can no longer be pumped through the body properly, which can even lead to death. Electric impulses – also called action potentials – run through the heart and cause heart muscle cells to contract consecutively. Cardiac arrythmias can develop when the shape and conduction of action potentials are disturbed. However, much is still unknown about how this works exactly. The groups of Jeroen Bakkers (Hubrecht Institute/UMC Utrecht), Teun de Boer (UMC Utrecht) and Kelly Smith (University of Melbourne) investigate how the heart rhythm is regulated and which genes are involved in this.
In their new paper, published in PNAS, the researchers show that the Tmem161b protein plays an important role in the regulation of the cardiac rhythm in at least two species: the zebrafish and the mouse. The researchers observed a disturbed cardiac rhythm in a group of zebrafish embryos and the cause was traced back to a mutation in Tmem161b. Likewise, mice that carried a mutation in this gene displayed abnormalities in heart function. Homozygous mutations – that is, mutations that occur on both copies of the gene – are incompatible with life; animals with this double mutation in Tmem161b die prematurely. This also appears to be the case in humans. Animals with a heterozygous mutation – a mutation on one copy of the gene – mature, but then appear more susceptible to developing cardiac arrythmias. “We do not know yet whether this is also the case in humans. Further research is necessary to elucidate this,” says Lotte Koopman, researcher on the project.
Specialized measurements allowed the researchers to measure the electrical currents in heart muscle cells. These were found to be seriously affected in both mice and zebrafish. “Mutations in the Tmem161b gene influence the calcium and potassium currents in the heart muscle cells, which can cause spontaneous disturbances in heart rhythm,” explains Koopman. The calcium and potassium currents play an important role in the formation of action potentials, which ensure that the heart beats rhythmically. “Tmem161b is therefore directly involved in the regulation of the heart rhythm, at least in zebrafish and mice,” says Koopman.
The newly discovered function of Tmem161b and the effect of the mutation do raise new questions for the researchers. “We now know that Tmem161b regulates calcium and potassium currents, but we do not yet know how that happens exactly and which genes may additionally be involved. This needs to be researched further. And it is important to investigate the function of Tmem161b and the effect of possible mutations in humans as well. Hopefully, this will enable us to develop better diagnostics and additional treatments for cardiac arrythmias in the long term.”
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, Angela Jeanes, Gregory J Baillie, Scott Paterson, Samuel D. Robinson, Laurence Garric, Cas Simons, Irina Vetter, Benjamin M Hogan, Teun P de Boer, Jeroen Bakkers and Kelly A Smith. PNAS (2021).
Jeroen Bakkers is group leader at the Hubrecht Institute and professor of Molecular Cardiogenetics at the University Medical Center Utrecht.
Teun de Boer is associate professor at the Department of Medical Physiology at the University Medical Center Utrecht.
Kelly Smith is lab head in the Department of Physiology at the University of Melbourne.
*Photo: The expression of Tmem161b in heart muscle cells of a young zebrafish is depicted in green. Original image in Koopman et al., PNAS, 2021.
