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Human Molecular Genetics Advance Access published online on June 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi221
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Published by Oxford University Press 2005
Received May 2, 2005
Revised May 24, 2005
Accepted June 16, 2005

Article

Expression of a LMNA-N195K Variant of A-Type Lamins Results in Cardiac Conduction Defects and Death in Mice

Leslie C. Mounkes 1, Serguei V. Kozlov 1, Jeffrey N. Rottman 2, and Colin L. Stewart 3*

1 National Cancer Institute, Cancer and Developmental Biology Laboratory, Frederick, MD 21702
2 Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6300
3 NCI-Frederick, Cancer and Developmental Biology Laboratory, P.O. Box B, Building 539, Room 121A

* To whom correspondence should be addressed.
Colin L. Stewart, E-mail: stewartc{at}ncifcrf.gov


  Abstract

The nuclear lamina is an approximately 10 nm thick proteinaceous layer underlying the inner nuclear membrane. The A-type lamins, nuclear intermediate filament proteins encoded by the LMNA gene, are basic components of the nuclear lamina. Mutations in LMNA are associated with the laminopathies, congenital diseases affecting tissue regeneration and homeostasis. One of these laminopathies associated with missense mutations in LMNA is dilated cardiomyopathy with conduction system disease (DCM-CD1). To understand how the laminopathies arise from different mutations in a single gene, we derived a mouse line by homologous recombination expressing the Lmna-N195K variant of the A-type lamins with an asparagine-to-lysine substitution at amino acid 195, which causes DCM in humans. This mouse line shows characteristics consistent with dilated cardiomyopathy with conduction system disease (DCM-CD1). Continuous EKG monitoring of cardiac activity demonstrated that LmnaN195K/N195K mice die an early death due to arrhythmia. By immunofluorescence and Western analysis, the transcription factor Hf1b/Sp4, and the gap junction proteins connexin 40 and connexin 43, were mis-expressed and/or mis-localized in LmnaN195K/N195K hearts. Desmin staining revealed a loss of organization at sarcomeres and intercalated disks. Mutations within the LMNA gene may therefore cause cardiomyopathy by disrupting the internal organization of the cardiomyocyte, and/or altering the expression of transcription factors essential to normal cardiac development, aging or function.


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