Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm

Cerrone, Marina; Montnach, Jérôme; Lin, Xianming; Zhao, Yan; Zhang, Mingliang; Agullo‐Pascual, Esperanza; Leo‐Macias, Alejandra; Alvarado, Francisco; Dolgalev, Igor; Karathanos, Thomas V.; Malkani, K; Opbergen, Chantal J.M. van; Bavel, Joanne J. A. van; Yang, Hua; Vásquez, Carolina; Tester, David J.; Fowler, Steven J.; Liang, Feng-Xia; Rothenberg, Eli; Heguy, Adriana; Morley, Gregory E.; Coetzee, William A.; Trayanova, Natalia A.; Ackerman, Michael J.; Veen, Toon A.B. van; Valdivia, Héctor H.; Delmar, Mario

doi:10.1038/s41467-017-00127-0

Cited by 168 publications

(276 citation statements)

References 60 publications

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“…In a PKP2 knockout mouse model, RYR2, ANK2, CACNA1C, and TRDN expression were reduced, as well as protein levels of calsequestrin-2, leading to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias because of loss of cell-cell communication [109]. However, the role of variants in this gene is disputed, as family segregation studies are lacking [17,110].…”

Section: Calcium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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Section: Calcium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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“…Recent studies show that ID proteins are also involved in modulation of transcription pathways fundamental for homeostasis within cardiomyocytes. Specifically, the transcription of genes involved in the intracellular calcium (Ca 2+ ) homeostasis can be modified by the expression of PKP2 (Cerrone et al, 2017;Montnach et al, 2018). Besides that, PKP2 loss provokes non-transcriptional related Ca 2+ handling dysregulation, via ID-located Cx43 hemichannels and a change in the phosphorylation state of the Ryanodine receptor (RyR2) (Kim et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

Self Cite

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Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.

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“…Also, some researchers observed fibrosis in the myocardium of the peroxisomal proliferator‐activated receptor α (PPARα)‐null mice . In addition, large lipid droplets deposit also leaded to ID remodeling, a phenomenon confirmed by immunofluorescence staining (Supporting Information Figure S2) which ultimately facilitated a highly arrhythmogenic state …”

Section: Discussionmentioning

confidence: 92%

The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations

Rao

Guo

et al. 2019

Clinical Genetics

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Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibrofatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one‐third of ACM probands. To investigate this further, we performed whole genome sequencing in 14 mutation‐negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G > A, p.G82D), a rate‐limiting enzyme that hydrolyzes triglycerides into fatty acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss of function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant cosegregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knockin mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12 weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by the age of 14 weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G > A, p.G82D) associated with a recessive form of ACM.

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Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm

Cited by 168 publications

References 60 publications

Brugada Syndrome: Oligogenic or Mendelian Disease?

Brugada Syndrome: Oligogenic or Mendelian Disease?

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations

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