Deciphering PLN-R14del cardiomyopathy

Cardiomyopathies comprise a heterogeneous group of heart muscle disorders that may result in contractile dysfunction, arrhythmias, heart failure, and sudden cardiac death. A clinically important inherited form is phospholamban (PLN)-related cardiomyopathy, caused by the pathogenic PLN-R14del variant. This variant is relatively common in the Netherlands and is characterized by clinical variability, suggesting a complex and incompletely understood pathogenesis.
This thesis aimed to elucidate the molecular and pathophysiological mechanisms underlying PLN-R14del cardiomyopathy and to identify potential therapeutic targets. Five research lines were pursued: a comprehensive overview of pathogenic PLN variants, assessment of cardiac stress as a disease modifier, development of an inducible mouse model, evaluation of PLN-targeting antisense oligonucleotides, and in silico modelling of distinct PLN complexes.
The findings show that PLN-related cardiomyopathy is not a uniform disease entity, but that different PLN variants may induce disease through variant-specific mechanisms. For PLN-R14del, cardiac stress in a mouse model did not substantially accelerate disease onset. In the inducible mouse model, the earliest detectable abnormality was the formation of PLN-positive clusters within the sarco/endoplasmic reticulum, preceding cardiac dysfunction. Proteomic and transcriptomic analyses indicated disruption of proteostasis and quality-control pathways. Furthermore, antisense oligonucleotide treatment produced dose-dependent improvements in cardiac function, remodelling, survival, and PLN-cluster reduction. In silico analyses supported these results by indicating that pentameric PLN complexes are particularly sensitive to PLN silencing.
Together, these findings support a revised disease concept in which PLN-R14del cardiomyopathy is primarily regarded as a structural disorder of the sarco/endoplasmic reticulum, offering perspectives for early detection and mechanism-driven therapy.