Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Cordula M Wolf; Libin Wang; Ronny Alcalai; Anne Pizard; Patrick G Burgon; Ferhaan Ahmad; Megan Sherwood; Dorothy M Branco; Hiroko Wakimoto; Glenn I Fishman; Vincent See; Colin L Stewart; David A Conner; Charles I Berul; Christine E Seidman; J.G Seidman

doi:10.1016/j.yjmcc.2007.11.008

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Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Journal article

Peer reviewed

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Cordula M Wolf, Libin Wang, Ronny Alcalai, Anne Pizard, Patrick G Burgon, Ferhaan Ahmad, Megan Sherwood, Dorothy M Branco, Hiroko Wakimoto, Glenn I Fishman, …

Journal of molecular and cellular cardiology, Vol.44(2), pp.293-303

02/2008

DOI: 10.1016/j.yjmcc.2007.11.008

PMCID: PMC3011813

PMID: 18182166

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Abstract

Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna+/− mice. Despite one normal allele, Lmna+/− mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna+/− mice but, by 4 weeks of age, atrioventricular (AV) nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10-week-old Lmna+/− mice showed AV conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month-old Lmna+/− mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna+/− mice revealed DCM; in some mice this occurred without overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately, these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.

Cardiac conduction system

Laminopathies

Arrhythmia

Dilated cardiomyopathy

Heart block

Details

Title: Subtitle: Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease
Creators: Cordula M Wolf - Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
Libin Wang - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Ronny Alcalai - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Anne Pizard - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Patrick G Burgon - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Ferhaan Ahmad - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Megan Sherwood - Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
Dorothy M Branco - Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
Hiroko Wakimoto - Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
Glenn I Fishman - Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA
Vincent See - Cardiology, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118, USA
Colin L Stewart - Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA
David A Conner - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Charles I Berul - Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
Christine E Seidman - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
J.G Seidman - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.44(2), pp.293-303
DOI: 10.1016/j.yjmcc.2007.11.008
PMID: 18182166
PMCID: PMC3011813
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier Ltd
Language: English
Date published: 02/2008
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025564402771

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