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Tnni3k modifies disease progression in murine models of cardiomyopathy.

Publication ,  Journal Article
Wheeler, FC; Tang, H; Marks, OA; Hadnott, TN; Chu, P-L; Mao, L; Rockman, HA; Marchuk, DA
Published in: PLoS Genet
September 2009

The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention.

Duke Scholars

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

September 2009

Volume

5

Issue

9

Start / End Page

e1000647

Location

United States

Related Subject Headings

  • Systole
  • Survival Analysis
  • RNA, Messenger
  • RNA Stability
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Myocardium
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice
 

Citation

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MLA
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Wheeler, F. C., Tang, H., Marks, O. A., Hadnott, T. N., Chu, P.-L., Mao, L., … Marchuk, D. A. (2009). Tnni3k modifies disease progression in murine models of cardiomyopathy. PLoS Genet, 5(9), e1000647. https://doi.org/10.1371/journal.pgen.1000647
Wheeler, Ferrin C., Hao Tang, Odessa A. Marks, Tracy N. Hadnott, Pei-Lun Chu, Lan Mao, Howard A. Rockman, and Douglas A. Marchuk. “Tnni3k modifies disease progression in murine models of cardiomyopathy.PLoS Genet 5, no. 9 (September 2009): e1000647. https://doi.org/10.1371/journal.pgen.1000647.
Wheeler FC, Tang H, Marks OA, Hadnott TN, Chu P-L, Mao L, et al. Tnni3k modifies disease progression in murine models of cardiomyopathy. PLoS Genet. 2009 Sep;5(9):e1000647.
Wheeler, Ferrin C., et al. “Tnni3k modifies disease progression in murine models of cardiomyopathy.PLoS Genet, vol. 5, no. 9, Sept. 2009, p. e1000647. Pubmed, doi:10.1371/journal.pgen.1000647.
Wheeler FC, Tang H, Marks OA, Hadnott TN, Chu P-L, Mao L, Rockman HA, Marchuk DA. Tnni3k modifies disease progression in murine models of cardiomyopathy. PLoS Genet. 2009 Sep;5(9):e1000647.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

September 2009

Volume

5

Issue

9

Start / End Page

e1000647

Location

United States

Related Subject Headings

  • Systole
  • Survival Analysis
  • RNA, Messenger
  • RNA Stability
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Myocardium
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice