151 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 INTRODUCTION In 2006, the deletion of arginine 14 (p.Arg14del) within the phospholamban protein (PLNR14del) was discovered to cause severe cardiomyopathy in members of a Greek family.1 Since then, this mutation has been identified in thousands of cardiomyopathy patients across various countries, including the USA, Canada, China, Japan, Vietnam, Italy, Germany, Spain, and the Netherlands (Figure 1).1–8 Notably, in the Dutch population, the PLN-R14del founder mutation has emerged as one of the most prevalent genetic mutations associated with cardiomyopathy. More than 1600 carriers have been identified so far, and this number continues to grow.9,10 In the Netherlands, PLN-R14del is responsible for approximately 10% to 15% of patients with dilated cardiomyopathy (DCM) and 15% with arrhythmogenic cardiomyopathy (ACM)11. Remarkably, this mutation accounts for about 25% of the annual heart transplants performed in the Netherlands, underlining its significant impact on cardiac health.10 Figure 1. World map illustrating the global distribution of PLN-R14del carriers, which have been identified in 10 different countries around the world (dark blue color). N= number of patients described per study. Phospholamban is a small protein consisting of 52 amino acids and is encoded by the PLN gene. Its primary role is the regulation of the calcium pump known as Sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a) within cardiomyocytes. The normal function of PLN has been extensively reviewed.12,13 Nevertheless, the precise mechanisms and implications of the PLN-R14del mutation in causing heart disease remain unclear and subject to controversy, warranting ongoing research efforts. In this review, we systematically summarize all studies describing the PLN-R14del mutation and discuss the pathological phenotypes in addressing the PLN-R14del cardiomyopathy.
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