Why the study?
Pathogenic variants in desmosomal genes cause both mechanical intercalated disc dysfunction and pro-arrhythmic mechanisms, prompting a detailed examination of their molecular interactions and clinical phenotypes.
This review highlights that desmosomal gene variants in arrhythmogenic cardiomyopathy drive not only mechanical failure and fibrofatty replacement but also direct pro-arrhythmic molecular mechanisms.
May refine ACM phenotyping; extends mechanistic models but leaves targeted therapies open.
Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosome: plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), plakoglobin (JUP) and desmoplakin (DSP). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes.
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Costa et al. (2020) studied this question.
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