The K219T-Lamin Mutation Induces Conduction Defects Through Epigenetic Inhibition of SCN5A in Human Cardiac Laminopathy

Overview

Journal Nat Commun

Specialty Biology

Date 2019 May 24

PMID 31118417

Citations 64

Authors

Nicolo 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

Elisa Di Pasquale

Affiliations

Soon will be listed here.

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 Na1.5 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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