Human Molecular Genetics Advance Access originally published online on September 20, 2005
Human Molecular Genetics 2005 14(21):3179-3189; doi:10.1093/hmg/ddi349
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Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival
1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA, 2University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA and 3New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
* To whom correspondence should be addressed. Fax: +1 2072886073; Email: gac{at}jax.org
Received August 9, 2005; Accepted September 12, 2005
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.
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