Skip Navigation



Human Molecular Genetics Advance Access published online on September 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi349
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
14/21/3179    most recent
ddi349v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Maddatu, T. P.
Right arrow Articles by Cox, G. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maddatu, T. P.
Right arrow Articles by Cox, G. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 9, 2005
Revised September 12, 2005
Accepted September 12, 2005

Article

Dilated cardiomyopathy (DCM) in the nmd mouse: Transgenic rescue and QTLs that improve cardiac function and survival

Terry P. Maddatu 1, Sean M. Garvey 2, David G. Schroeder 1, Wiedong Zhang 1, Soh-Yule Kim 3, Anthony I. Nicholson 1, Crystal J. Davis 1, and Gregory A. Cox 1*

1 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
2 University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA
3 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

* To whom correspondence should be addressed.
Gregory A. Cox, E-mail: gac{at}jax.org


  Abstract

Mutations in the immunoglobulin mu binding protein 2 (Ighmbp2) gene cause motor neuron disease and dilated cardiomyopathy (DCM) in the neuromuscular degeneration (nmd) mouse, and spinal muscular atrophy with respiratory distress (SMARD1) in humans. To investigate the role of IGHMBP2 in the pathogenesis of DCM, we generated transgenic mice expressing the full-length Ighmbp2 cDNA specifically in myocytes under the control of the mouse titin promoter. This tissue-specific transgene increased the lifespan of nmd mice up to 8 fold by preventing primary DCM and showed complete functional correction as measured by ECG, echocardiography and plasma CK-MB. Double-transgenic nmd mice expressing Ighmbp2 both in myocytes and neurons display correction of both DCM and motor neuron disease resulting in an essentially wild-type appearance. Additionally, quantitative trait locus (QTL) analysis was undertaken to identify genetic modifier loci responsible for preservation of cardiac function and a marked delay in the onset of cardiomyopathy in a CAST/EiJ backcross population. Three major CAST-derived cardiac modifiers of nmd were identified on Chromosomes 9, 10, and 16, that account for over 26% of the genetic variance and that continue to suppress the exacerbation of cardiomyopathy, otherwise resulting in early death, as incipient B6.CAST congenics. Overall our results verify the tissue-specific requirement for IGHMBP2 in cardiomyocyte maintenance and survival, and describe genetic modifiers that can alter the course of DCM through cardiac functional adaptation and physical remodeling in response to changes in load and respiratory demand.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
T. O. Gavrilina, V. L. McGovern, E. Workman, T. O. Crawford, R. G. Gogliotti, C. J. DiDonato, U. R. Monani, G. E. Morris, and A. H.M. Burghes
Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect
Hum. Mol. Genet., April 15, 2008; 17(8): 1063 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
A. M. Kaindl, U.-P. Guenther, S. Rudnik-Schoneborn, R. Varon, K. Zerres, M. Schuelke, C. Hubner, and K. von Au
Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
J Child Neurol, February 1, 2008; 23(2): 199 - 204.
[Abstract] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.