TY - JOUR
T1 - Investigating LMNA-related dilated cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes
AU - Shemer, Yuval
AU - Mekies, Lucy N.
AU - Ben Jehuda, Ronen
AU - Baskin, Polina
AU - Shulman, Rita
AU - Eisen, Binyamin
AU - Regev, Danielle
AU - Arbustini, Eloisa
AU - Gerull, Brenda
AU - Gherghiceanu, Mihaela
AU - Gottlieb, Eyal
AU - Arad, Michael
AU - Binah, Ofer
N1 - Funding Information:
Funding: The work was supported by the Israel Science Foundation (ISF 824/19 grant to O.B. and E.G.), The Rappaport Family Institute for Research in the Medical Science (01012020RI grant to O.B. and E.G.), Niedersachsisches Ministerium: Medizinischen Hochschule Hannover (MHH) (11- 76251-99-16/14 grant to O.B. and E.G.), and the Interdisciplinary Center for Clinical Research, Würzburg (project E-338 to B.G.).
Funding Information:
The work was supported by the Israel Science Foundation (ISF 824/19 grant to O.B. and E.G.), The Rappaport Family Institute for Research in the Medical Science (01012020RI grant to O.B. and E.G.), Niedersachsisches Ministerium: Medizinischen Hochschule Hannover (MHH) (11 76251-99-16/14 grant to O.B. and E.G.), and the Interdisciplinary Center for Clinical Research, W?rzburg (project E-338 to B.G.).We would like to thank Natalie Pluta and Konstantinos Kolokotronise (Institute of Human Genetics, W?rzburg, Germany) for their technical help performing the exome sequencing and data analysis. We would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about (accessed on 1 September 2019). We would like to thank Liat Linde, Ronit Hod and Elizabeta Ginzburg (the Genomics Center of the Biomedical Core Facility, Ruth and Bruce Rappaport Faculty of Medicine, Technion?Israel Institute of Technology, Haifa, Israel) for their technical help performing the RNA sequencing and data analysis. We would like to thank Lena Milman (Ruth and Bruce Rappaport Faculty of Medicine, Technion?Israel Institute of Technology, Haifa, Israel) for her excellent technical assistance.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
AB - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
KW - Arrhythmia
KW - Dilated cardiomyopathy
KW - Electrophysiology
KW - IPSC-CMs
KW - LMNA
UR - http://www.scopus.com/inward/record.url?scp=85110765777&partnerID=8YFLogxK
U2 - 10.3390/ijms22157874
DO - 10.3390/ijms22157874
M3 - Article
C2 - 34360639
AN - SCOPUS:85110765777
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 15
M1 - 7874
ER -