Molecular insights on arrhythmogenic cardiomyopathy: assessment of premature termination codons in desmosomal genes and variants reclassification

Vallverdú Prats, Marta
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Arrhythmogenic cardiomyopathy (ACM) is an entity that groups different clinical forms of hereditable cardiac diseases that are associated to ventricular arrhythmia and sudden cardiac death. The main cases are characterized by the substitution of cardiomyocytes with fibro-fatty tissue. Rare genetic variants in desmosomal genes are the principal genetic cause, but some non-desmosomal genes are also associated with ACM. The family history is an important parameter for the diagnosis of the disease, so many studies are increasingly focused on describing the role of genetic variants and its associated molecular alterations. However, there are still uncertainties to be answered on that direction. The present thesis has the aim to describe the molecular mechanisms and functional consequences triggered by premature termination codons (PTC) in desmosomal genes using a CRISPR edited cellular line as an ACM model. Moreover, it also aims to determine how updated data of genetic ACM-associated variants impacts its classification. Our results on the cellular model showed that a PTC in 5’ region of DSP and JUP triggers reinitation of translation due to an optimal genomic context of alternative ATG in-frame while PTC in 5’ located in PKP2, DSG2 and DSC2 activates nonsense-mediated decay causing the absence of the protein expression associated to a more deleterious effect. Functionally, the absence of the studied desmosomal genes triggered alterations in calcium handling. Specifically, the loss of PKP2, DSG2 or DSC2 causes a higher amplitude of the calcium peak while DSP loss triggers a quicker calcium uptake with a shorter amplitude of the peak. Finally, this thesis also described that new data of genetic variants associated to ACM, such as updated global frequencies, contribute to reduce the uncertainty in terms of variant classification. In summary, although ACM physiopathology is complex and there are still lots of questions to be solved, the present thesis elucidated some of the key molecular pathophysiological mechanisms underlying the disease pointing into some directions worth to be explored in future ACM studies ​
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