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Salvarani, Nicolò; Crasto, Silvia; Miragoli, Michele; Bertero, Alessandro; Paulis, Marianna; Kunderfranco, Paolo; Serio, Simone; Forni, Alberto; Lucarelli, Carla; Dal Ferro, Matteo; Larcher, Veronica; Sinagra, Gianfranco; Vezzoni, Paolo; Murry, Charles E; Faggian, Giuseppe; Condorelli, Gianluigi; Di Pasquale, Elisa
Nature communications, 05/2019, Letnik: 10, Številka: 1Journal Article
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 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.
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