The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy. The molecular pathomechanisms remain incompletely understood. Patient fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSC), isogenic controls were established using CRISPR/Cas9 genome editing, and differentiated into hiPSC-cardiomyocytes. Patient-derived PLN p.Arg14del hiPSC-cardiomyocytes showed lower force, but, other than expected, no sarcoplasmic dysfunction.
Subsequent studies revealed lower abundance of endoplasmic reticulum (ER)-, ribosomal and mitochondrial proteins in PLN p.Arg14del hiPSC-cardiomyocytes, in combination with morphological and functional alterations of the ER/mitochondrial compartment and markers of oxidative stress.
In cardiac tissue samples from PLN p.Arg14del patients, these observations were corroborated. This study postulates pathological alteration of the ER/mitochondrial compartment as a novel disease mechanism in patients with PLN p.Arg14del cardiomyopathy.