Credit: Aryan Vink and Petra van der Kraak. Copyright: UMC Utrecht.

22 March 2023

From mutation to arrhythmia: desmosomal protein breakdown as an underlying mechanism of cardiac disease

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Mutations in genes that form the desmosome are the most common cause of the cardiac disease arrhythmogenic cardiomyopathy (ACM), which affects one in 2000 to 5000 people worldwide. Researchers from the group of Eva van Rooij now discovered how a mutation in the desmosomal gene plakophilin-2 leads to ACM. They found that the structural and functional changes in ACM hearts caused by a plakophilin-2 mutation are the result of increased desmosomal protein degradation. The results of this study, published in Science Translational Medicine on March 22nd 2023, further our understanding of ACM and could contribute to the development of new therapies for this disease.

Figure 1: Patches of fibrosis (blue) and fat (white) tissue in the heart of an ACM patient. Heart muscle cells are shown in red. Credit: Aryan Vink and Petra van der Kraak. Copyright: UMC Utrecht.


ACM is a progressive and inheritable cardiac disease for which currently no treatments exist to halt its progression. Although patients initially do not experience any symptoms, they are at a higher risk of arrhythmias and resulting sudden cardiac arrest. As the disease progresses, patches of fibrotic and fat tissue form in the heart which can lead to heart failure. At this stage, patients require a heart transplantation as treatment.

Figure 2: Disorganized plakophilin-2 (PKP2) in severely fibrotic regions of the heart of ACM patients. Top panels show fibrotic tissue (blue), fat tissue (white) and heart muscle cells (red) of control and ACM patient hearts. Bottom panels show the protein localization of plakophilin-2 in the hearts of a healthy individual and an ACM patient. Credit: Petra van der Kraak. Copyright: UMC Utrecht.

Over 50% of all ACM cases are caused by a mutationAn error in the DNA. Mutations can, among other things, arise if the DNA is copied incorrectly or through external influences. For example, tumor cells often contain mutations that are beneficial for their growth. in one of the desmosomal genesA small piece of DNA with a specific function. For example, genes determine which color our eyes have and whether we have curly or straight hair. In a human cell, the DNA contains about 30.000 genes, each having a specific function. Genes are hereditary and can therefore be passed on to offspring., which together form complex protein structures known as desmosomes. Desmosomes form “bridges” between individual heart muscle cells, allowing the cells to contract in a coordinated manner. Most of the desmosomal mutations that cause ACM occur in a gene called plakophilin-2. Nevertheless, very little is known on how mutations in this gene lead to the disease. To change this, the Van Rooij lab first studied human heart samples from ACM patients carrying mutations in the plakophilin-2 gene. “We saw lower levels of all desmosomal proteins and disorganized desmosomal protein staining in fibrotic areas of the ACM hearts,” says Jenny (Hoyee) Tsui, first author on the paper. Tsui: “In addition, cultured 3D heart muscle tissue originating from a patient with a plakophilin-2 mutation, was unable to continue beating at higher pacing rates, which resembles arrhythmias seen in the clinic.”

Figure 3: Plakophilin-2 levels (red) are reduced in the hearts of ACM mice compared to healthy control mice. Heart muscle cells are shown in green, cell nuclei are shown in blue. Credit: Jenny (Hoyee) Tsui. Copyright: Hubrecht Institute.
ACM in mice

The researchers then used a genetic tool called CRISPR/Cas9A technique that researchers can use to cut the DNA in a very specific place, to make a change there. This way, researchers can study the effect of a specific change in the DNA. to introduce the human plakophilin-2 mutation in mice to mimic ACM. This allowed them to study progression of the disease in more detail. They observed that old ACM mice carrying this mutation had lower levels of desmosomal proteins and heart relaxation issues, similar to ACM patients. Strikingly, the researchers discovered that the mutation lowered levels of desmosomal proteins even in young, healthy mice of which the heart contracted normally. From this they concluded that a loss of desmosomal proteins could underlie the onset of ACM caused by a plakophilin-2 mutation.

Protein degradation

The researchers then moved on to explain the loss of desmosomal proteins. For this they studied both RNA and protein levels in their ACM mice. “The levels of desmosomal proteins were lower in our ACM mice compared to healthy control mice. However, the RNA levels of these genes were unchanged. We discovered that these surprising findings are the result of increased protein degradation in ACM hearts,” explains Sebastiaan van Kampen, co-first author of the paper. Tsui adds:When we treated our ACM mice with a drug that prevents protein degradation, the levels of desmosomal proteins were restored. More importantly, the restored levels of desmosomal proteins improved calcium handling of heart muscle cells, which is vital for their normal function”.


Towards new therapies

The results of this study, published in Science Translational Medicine, raise new insights into ACM development and indicate that protein degradation could be an interesting target for future therapies. “Protein degradation occurs in every cell of our body and is crucial for the function of these cells. To overcome side-effects of future therapies we will need to develop drugs that prevent degradation of desmosomal proteins in heart muscle cells specifically,” explains Eva van Rooij, group leader at the Hubrecht Institute and last author of the study. More research is thus needed to realize this. In the future, these new specific drugs could potentially be used to halt the onset and prevent progression of ACM.


Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy. Hoyee Tsui#, Sebastiaan J. van Kampen#, Su Ji Han, Viviana Meraviglia, Willem B. van Ham, Simona Casini, Petra van der Kraak, Aryan Vink, Xiaoke Yin, Manuel Mayr, Alexandre Bossu, Gerard A. Marchal, Jantine Monshouwer-Kloots, Joep Eding, Danielle Versteeg, Hesther de Ruiter, Karel Bezstarosti, Judith Groeneweg, Sjoerd J. Klaasen, Linda W. van Laake, Jeroen A.A. Demmers, Geert J.P.L. Kops, Christine L. Mummery, Toon A.B. van Veen, Carol Ann Remme, Milena Bellin, Eva van Rooij. Science Translational Medicine, 2023.

# = These authors contributed equally.

This publication is the result of a collaboration between the group of Eva van Rooij (Hubrecht Institute) and groups from the LUMC, UMC Utrecht, UMC Amsterdam, King’s College London and the Erasmus MC. The study was funded by the Dutch CardioVascular Alliance with support of the Dutch Heart Foundation.

Picture of Eva Van Rooij



Eva van Rooij is group leader at the Hubrecht Institute and professor of Molecular Cardiology at the UMC Utrecht.