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

Nicolò Salvarani, Silvia Crasto, Michele Miragoli, Alessandro Bertero, Marianna Paulis, Paolo Kunderfranco, Simone Serio, Alberto Forni, Carla Lucarelli, Matteo Dal Ferro, Veronica Larcher, Gianfranco Sinagra, Paolo Vezzoni, Charles E. Murry, Giuseppe Faggian, Gianluigi Condorelli () and Elisa Di Pasquale ()
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Nicolò Salvarani: National Research Council of Italy
Silvia Crasto: National Research Council of Italy
Michele Miragoli: National Research Council of Italy
Alessandro Bertero: University of Washington
Marianna Paulis: National Research Council of Italy
Paolo Kunderfranco: Humanitas Clinical and Research Center – IRCCS
Simone Serio: Humanitas Clinical and Research Center – IRCCS
Alberto Forni: University of Verona
Carla Lucarelli: University of Verona
Matteo Dal Ferro: “Ospedali Riuniti” and University of Trieste
Veronica Larcher: Humanitas Clinical and Research Center – IRCCS
Gianfranco Sinagra: “Ospedali Riuniti” and University of Trieste
Paolo Vezzoni: National Research Council of Italy
Charles E. Murry: University of Washington
Giuseppe Faggian: University of Verona
Gianluigi Condorelli: National Research Council of Italy
Elisa Di Pasquale: National Research Council of Italy

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09929-w

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