ArticleHuman molecular genetics2021
The prevalent I686T human variant and loss-of-function mutations in the cardiomyocyte-specific kinase gene TNNI3K cause adverse contractility and concentric remodeling in mice.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- High levels of the cardiomyocyte-specific kinase Tnni3k impair zebrafish heart regeneration by driving chronic myocardial inflammation.bioRxiv : the preprint server for biology · 2026Article
- Tnni3k Is Cardioprotective in Viral Myocarditis.Journal of cardiovascular development and disease · 2026Article
- RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing.Cardiovascular research · 2024Article
- A kinase-dead natural polymorphism in the caninemicroPublication biology · 2024Article
- Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development.Journal of molecular and cellular cardiology · 2024Article
- Genetic Burden ofCirculation. Genomic and precision medicine · 2023Article
- Cardiomyocyte ploidy is dynamic during postnatal development and varies across genetic backgrounds.Development (Cambridge, England) · 2023Article
- Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy.The Journal of clinical investigation · 2022Article
- RBPMS is an RNA-binding protein that mediates cardiomyocyte binucleation and cardiovascular development.Developmental cell · 2022Article
- The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment.International journal of molecular sciences · 2021Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling, characterized by ventricular wall thickening and substantial reduction of cardiomyocyte aspect ratio. This pathology occurs in mice carrying a Tnni3k null allele, a K489R point mutation rendering the protein kinase-dead, or an allele corresponding to human I686T, the most common human non-synonymous TNNI3K variant, which is hypomorphic for kinase activity. Mutant mice develop these conditions in the absence of fibrosis or hypertension, implying a primary cardiomyocyte etiology. In culture, mutant cardiomyocytes were impaired in contractility and calcium dynamics and in protein kinase A signaling in response to isoproterenol, indicating diminished contractile reserve. These results demonstrate a beneficial function of TNNI3K in the adult heart that might explain its evolutionary conservation and imply that human TNNI3K variants, in particular the widespread I686T allele, may convey elevated risk for altered heart geometry and hypertrophy.
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