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 Nav1.5 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 / Salvarani, N.; Crasto, S.; Miragoli, M.; Bertero, A.; Paulis, M.; Kunderfranco, P.; Serio, S.; Forni, A.; Lucarelli, C.; Dal Ferro, M.; Larcher, V.; Sinagra, G.; Vezzoni, P.; Murry, C. E.; Faggian, G.; Condorelli, G.; Di Pasquale, E.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 2267. [10.1038/s41467-019-09929-w]

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

Miragoli M.;
2019-01-01

Abstract

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 Nav1.5 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.
2019
The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy / Salvarani, N.; Crasto, S.; Miragoli, M.; Bertero, A.; Paulis, M.; Kunderfranco, P.; Serio, S.; Forni, A.; Lucarelli, C.; Dal Ferro, M.; Larcher, V.; Sinagra, G.; Vezzoni, P.; Murry, C. E.; Faggian, G.; Condorelli, G.; Di Pasquale, E.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 2267. [10.1038/s41467-019-09929-w]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2861044
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