Phospholamban R14del disease: The past, the present and the future

Abstract

Arrhythmogenic cardiomyopathy affects significant number of patients worldwide and is characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Mutations in multiple genes with diverse functions have been reported to date including phospholamban (PLN), a key regulator of sarcoplasmic reticulum (SR) Ca2+ homeostasis and cardiac contractility. The PLN-R14del variant in specific is recognized as the cause in an increasing number of patients worldwide, and extensive investigations have enabled rapid advances towards the delineation of PLN-R14del disease pathogenesis and discovery of an effective treatment. We provide a critical overview of current knowledge on PLN-R14del disease pathophysiology, including clinical, animal model, cellular and biochemical studies, as well as diverse therapeutic approaches that are being pursued. The milestones achieved in <20 years, since the discovery of the PLN R14del mutation (2006), serve as a paradigm of international scientific collaboration and patient involvement towards finding a cure.

Unleashing the Power of Genetics: PLN Ablation, Phospholambanopathies and Evolving Challenges

“…Additional studies in iPSC-CMs indicated the beneficial effects of the small molecule activator BiX (BiP [binding immunoglobulin protein] inducer X) to stimulate UPR, the Ca 2+ sensor GCaMP6f or the Ca 2+ -binding protein parvalbumin, and the PLN double-mutant (L31A/I40A), which enhanced Ca 2+ transport. 19,23 However, a recent study reported a decrease in transient Ca 2+ amplitude in association with accelerated intracellular Ca 2+ dynamics in iPSC-CMs derived from 1 patient with this mutation. 21 Further studies are needed to explain these intriguing findings that are in sharp contrast with previous results.…”

“…18 Several PLN variants, associated with phospholambanopathies, exhibiting dilated cardiomyopathy or arrhythmogenic cardiomyopathy, have been found and include Arg9Cys, Arg9His, Arg25Cys, Leu39Ter, Glu2Ter, and Arg14del (Figure 1) and 2 promoter ones (−36 A>C and −42 C>G). 19 The homozygous Leu39stop was associated with a lack of PLN expression and pointed to distinct differences associated with PLN ablation between humans and mice.…”

“…More recently, the human R14del-PLN mutation has drawn considerable interest, and a PLN foundation has been organized by patients and carriers with the goal of supporting research and disseminating information. 19 The mutation is found only in the heterozygous state. Human carriers exhibit highly variable phenotypes, ranging from asymptomatic to cardiomyopathic with clinical features of both arrhythmogenic cardiomyopathy and dilated cardiomyopathy that may progress to HF and premature death.…”

“…21 Further studies are needed to explain these intriguing findings that are in sharp contrast with previous results. 19,20,22,23 To gain in vivo insights, 2 knockin mouse models were generated, and heterozygous animals, mimicking the human genotype, were characterized. 24,25 In one of them, the mouse PLN was replaced by the human sequence because the one amino acid difference between the mouse and human may affect PLN function.…”

Seeking for Regulatory Mechanisms of Phospholamban Expression

“…Of particular interest is PLN-R14del, the most prevalent cardiomyopathy-related mutation in the Netherlands, linked to the development of dilated and arrhythmogenic cardiomyopathies. 4 While not achieving full consensus, this mutation has been suggested to have a superinhibitory effect on SERCA2a activity due to its enhanced binding affinity for the pump. The resulting reduction of the SR Ca 2+ content and elevation of diastolic Ca 2+ have been indicated as potential contributors to the contractile impairment, diastolic dysfunction, and arrhythmogenesis observed in patients carrying this mutation.…”