Estudi de l’alliberació del calci intracel·lular en cardiomiòcits derivats de iPSC de pacients amb taquicàrdia ventricular polimòrfica catecolaminèrgica (CPVT)

Carreras Gorgals, David
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In a small region of the island of Gran Canaria, 11 cases of sudden cardiac death (SCD) were registered in emotional or physical stress situations in young individuals between 1994 and 2007 in four seemingly unrelated families. An extensive genealogical study allowed to connect the four families within a large family tree of more than 2000 members with a common ancestor born in 1749. Genetic studies identified a mutation in the type 2 ryanodine receptor (RYR2) gene RYR2_c.G1069A (RYR2_p.G357S) that was associated to the SCD cases in the family. The RYR2 gene is the main gene linked to lethal arrhythmia called catecholaminergic polymorphic ventricular tachycardia (CPVT). Initially, 179 living carriers of this mutation and 36 dead individuals were identified. Among the dead individuals, 6 were genotyped positive and the others had died under highly suggestive documented circumstances of CPVT. Studies performed with heterologous expression models, in which the expression of the mutated protein is induced, showed that the mutation promoted a gain of function in the activity of RYR2 under mimicked stress situations. Subsequent studies proposed that the variability in the penetrance and expressivity of the phenotype in the family could be explained by the decrease in the RYR2 protein amount caused by the mutation. The generation of cardiomyocytes from induced pluripotent stem cells (iPSC-CM) of individuals carrying the mutation, gave us the opportunity to determine the pathogenic effects of the mutation in a cellular relevant model, and how the individual genetic background could influence the phenotype of the disease ​
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