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Tnni3k modifies disease progression in murine models of cardiomyopathy
Ferrin C Wheeler1, Hao Tang, Odessa A Marks
1Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America.
Insights
Cardiac Troponin I-interacting kinase (Tnni3k) modifies heart disease progression. Reduced Tnni3k expression worsens cardiomyopathy, suggesting it as a therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Disease Pathogenesis
Background:
- Calsequestrin (Csq) transgenic mice show variable cardiomyopathy progression influenced by genetic background.
- Seven heart failure modifier (Hrtfm) loci identified that impact disease outcome.
Purpose of the Study:
- To identify the gene underlying the Hrtfm2 locus.
- To elucidate the role of Tnni3k in modulating heart failure progression.
Main Methods:
- Genomic analysis to identify the gene at Hrtfm2.
- RNA sequencing and splice site analysis to investigate Tnni3k transcript variants.
- Generation of transgenic mouse models (TNNI3K overexpression, TNNI3K/Csq double transgenic).
- Assessment of cardiac function and survival in mouse models.
- Evaluation of Tnni3k in a pressure-overload heart failure model.
Main Results:
- Tnni3k identified as the gene responsible for Hrtfm2.
- Reduced Tnni3k transcript levels in less susceptible strains due to an intronic SNP activating a cryptic splice site, leading to nonsense-mediated decay.
- Overexpression of human TNNI3K alone did not cause a cardiac phenotype.
- TNNI3K/Csq double transgenics exhibited severely impaired systolic function and reduced survival.
- Tnni3k expression accelerated disease progression in a pressure-overload heart failure model.
Conclusions:
- Tnni3k plays a critical role in modulating the progression of Csq-induced cardiomyopathy and pressure-overload heart failure.
- Deficiency in Tnni3k exacerbates heart disease.
- Tnni3k represents a potential novel therapeutic target for heart disease intervention.
Abstract:
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.
