RESUMO
AIMS: We identified an autosomal dominant nonsense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSCCMs) from an affected patient with R225X and another patient bearing LMNA frameshift mutation for drug screening. METHODS AND RESULTS: Higher prevalence of nuclear bleb formation and micronucleation was present in LMNA(R225X/WT) and LMNA(Framshift/WT) iPSCCMs. Under field electrical stimulation, percentage of LMNAmutated iPSCCMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the proapoptotic effects of field electric stimulation on the mutated LMNA iPSCCMs. CONCLUSION: LMNArelated DCM was modeled invitro using patientspecific iPSCCMs. Our results demonstrated that haploinsufficiency due to R225X LMNA nonsense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stressrelated ERK1/2 pathway.