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Series GSE36502 Query DataSets for GSE36502
Status Public on Jun 01, 2012
Title LmnaN195K Mouse Model
Organism Mus musculus
Experiment type Expression profiling by genome tiling array
Summary Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy.
 
Overall design 6 samples
 
Contributor(s) Balijepalli RC, Saqib A
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Submission date Mar 14, 2012
Last update date Jun 02, 2012
Contact name Ravi C Balijepalli
Organization name University of Wisconsin School of medicine and Public Health
Department Medicine
Lab Cellular and Molecular Arrhythmia Research Program
Street address 1300 University Ave, B370 SMI
City Madison
State/province WI
ZIP/Postal code 53719
Country USA
 
Platforms (1)
GPL9899 NimbleGen Mouse 2006-08-03_MM8_60mer_expr tiling design
Samples (6)
GSM895908 314143_Control-1_2009-05-08_532
GSM895909 314198_Control-2_2009-05-08_532
GSM895910 314136_Control-3_2009-05-08_532
Relations
BioProject PRJNA153447

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE36502_RAW.tar 120.2 Mb (http)(custom) TAR (of PAIR)
Processed data included within Sample table
Processed data provided as supplementary file

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