Journal Article

Dilated cardiomyopathy in the <i>nmd</i> mouse: transgenic rescue and QTLs that improve cardiac function and survival

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

in Human Molecular Genetics

Volume 14, issue 21, pages 3179-3189
Published in print November 2005 | ISSN: 0964-6906
Published online September 2005 | e-ISSN: 1460-2083 | DOI:
Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival

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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 creatine kinase-MB. Double-transgenic nmd mice expressing Ighmbp2 both in myocytes and in 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 the 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, which 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.

Journal Article.  5795 words.  Illustrated.

Subjects: Genetics and Genomics

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