13 General Introduction and Thesis Outline 1 the ACM patients in the Netherlands was caused by a deleterious mutation of the arginine 14 codon in the phospholamban (PLN) gene (p.Arg14del).9 Since the discovery of this mutation in a Greek family in 2006, thousands of patients have been identified in not only the Netherlands but also the USA, Canada, China, Germany, and Spain.10–15 PLN is a 52-amino acid protein located in the sarcoplasmic reticulum (SR) membrane that acts as a crucial reversible regulator of Ca2+ uptake in the CM.16 In contrast to wildtype PLN, a deletion of arginine 14 codon (R14del) in the PLN gene (PLN-R14del) disrupts the conformational changes upon phosphorylation, resulting in inhibition of PLN pentamer formation and thus constitutive inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase2a (SERCA2A/ATP2A2).12,17 Therefore, PLN-R14del has been associated with irreversible super-inhibition of SERCA2A activity, preventing the influx of calcium into the sarcoplasmic reticulum. This process, in theory, delays the Ca2+ reuptake and induces prolonged muscle contraction. The pathophysiological mechanism causes several clinical features, including a dilated and/or arrhythmogenic heart muscle and the presence of cardiac fibrofatty replacement18 and protein aggregates.19 Compared to other mutation carriers, patients with a PLN mutation have a higher frequency of left ventricle structural and functional abnormalities, and they show the most pronounced diminished left ventricle function detected by echocardiography and cardiac magnetic resonance imaging (MRI).20 Moreover, PLN-R14del hearts were compared with hearts with desmosomal, lamin A/C, sarcomeric, and desmin mutations and presented the highest amount of myocardial fibrosis, which is found in a distinct pattern in the posterolateral left ventricular wall.21 Ultimately, it has been determined that PLN-R14del mutation carriers have a higher incidence of malignant ventricular arrhythmias with left ventricular ejection fraction <45%, premature sudden cardiac death, and end-stage heart failure when compared to DCM patients that do not carry this pathogenic variant.22 This mutation presents a highly variable phenotype, ranging from asymptomatic to cardiomyopathic. Its awareness is rather low, therefore, thousands of people can be carriers unknowingly.20 This caveat is highly relevant because a substantial proportion of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. To raise awareness of the mutation phenotype and more efficiently identify carriers and possibly develop new therapies, it is key to better understand the pathological mechanisms underlying this disease. It remains unclear how exactly the PLN-R14del mutation leads to such severe cardiomyopathy and malignant arrhythmias. Unfortunately, despite almost two decades worth of research about PLN-R14del cardiomyopathy, targeted treatment for these patients is lacking. Currently, efforts to identify a tailored therapy are ongoing, using state-of-the-art technology and through synergistic collaborations. With the development in finding therapeutics for this specific cardiovascular disease, bridges will be built toward the utility of these strategies for a plethora of other diseases.
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