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Mutations in  LMNA , which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on  LMNA  to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T- LMNA , have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Na v 1.5 channel expression and increased binding of Lamin A/C to the promoter of  SCN5A , the channel’s gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at  SCN5A . CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and  SCN5A  expression. Thus, K219T- LMNA  cooperates with PRC2 in downregulating  SCN5A , leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy.

The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy