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DNA-binding protein SMUBP-2 (EC (EC (ATP-dependent helicase IGHMBP2) (Glial factor 1) (GF-1) (Immunoglobulin mu-binding protein 2) [SMBP2] [SMUBP2]


Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival.

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.

MeSH Terms

  • Analysis of Variance
  • Animals
  • Cardiomyopathy, Dilated
  • Connectin
  • Creatine Kinase, MB Form
  • Crosses, Genetic
  • Cytoskeletal Proteins
  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins
  • Electrocardiography
  • Longevity
  • Mice
  • Mice, Transgenic
  • Motor Neuron Disease
  • Muscle Cells
  • Muscle Proteins
  • Myocardium
  • Neurons
  • Promoter Regions, Genetic
  • Protein Kinases
  • Quantitative Trait Loci
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors
  • Transgenes