Functional abnormalities in iPSCs-derived cardiomyocytes generated from PLEKHM2-mutated patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a primary myocardial disease, leading to heart failure and excessive risk of sudden cardiac death with rather poorly understood pathophysiology. Parvari et al (2015) found that a cDNA 2156_2157delAG mutation in PLEKHM2 gene is associated with a severe recessive DCM and left ventricular non-compaction (LVNC) in a large Bedouin family. Fibroblasts isolated from these patients exhibited abnormal subcellular distribution of endosomes, Golgi apparatus, lysosomes and had impaired autophagy flux. Whether and how this mutation affect cardiomyocytes (CMs) in these patients remain unknown. Herein, we developed a novel "disease in a dish" model from PLEKHM2-mutated patient cells to investigate the mechanism behind this disease phenotype. We generated and characterized iPSCs-derived CMs from two patients and a healthy control from the same family. IPSCs-CMs from patients showed significantly low expression levels of contractile functional related genes compared to control and generated slowly beating foci with lower intracellular calcium amplitude and abnormal calcium transient kinetics. Autophagy flux of patient’s iPSC-CMs was impaired as determined from decrease in the accumulation of autophagosomes in response to chloroquine and rapamycin treatment, compared to control iPSC-CMs.

In summary, our findings indicate that the PLEKHM2 mutation, which is associated with impaired autophagy in cardiomyocytes and fibroblasts, may play a critical role in patients with DCM-LVNC disease.