The p.Arg14del mutation in the phospholamban (PLN) gene can cause dilated and arrhythmogenic cardiomyopathy, leading to heart failure. On average, disease onset is around the fifth decade, the prognosis is poor and mortality is high. As the exact disease mechanism is still unknown, no specific treatment for this cardiomyopathy is available and heart transplantation is often needed as a last resort.
Although PLN-R14del cardiomyopathy has been conceptualized as a disease caused by impaired calcium handling, this thesis of Nienke Stege revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum (S/ER) disorganization as an underlying disease mechanism. The novel mechanistic insights shown in this thesis, provide a new twist to PLN-R14del cardiomyopathy and suggest redirection of attention from interventions aimed at calcium dysregulation to restoring or maintaining proper S/ER structure. In a preclinical setting, DWORF overexpression could reduce S/ER disorganization and strongly delay disease development. Moreover, disease development could be halted by prevention of (mutant) PLN protein formation using antisense therapy directed against the PLN gene. These explorative interventions highlight the importance of targeting the earliest disease stage as possible to have the greatest treatment effect and the least unwanted side-effects. Further research is required to evaluate the clinical potential of the intervention strategies presented in this thesis.
