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    The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca2+ transient decay time, Ca2+ -load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow-up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end-stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non-failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca2+ -binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca2+ -scavenging, suggesting impaired local Ca2+ cycling as an important disease culprit. © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

    Citation

    Friederike Cuello, Anika E Knaust, Umber Saleem, Malte Loos, Janice Raabe, Diogo Mosqueira, Sandra Laufer, Michaela Schweizer, Petra van der Kraak, Frederik Flenner, Bärbel M Ulmer, Ingke Braren, Xiaoke Yin, Konstantinos Theofilatos, Jorge Ruiz-Orera, Giannino Patone, Birgit Klampe, Thomas Schulze, Angelika Piasecki, Yigal Pinto, Aryan Vink, Norbert Hübner, Sian Harding, Manuel Mayr, Chris Denning, Thomas Eschenhagen, Arne Hansen. Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation. EMBO molecular medicine. 2021 Jun 07;13(6):e13074

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    PMID: 33998164

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