ArticleHuman molecular genetics2014
TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 57 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
- Multifocal Atrial Tachycardia and Genetic Background-Guided Ablation Strategy for Atrial Fibrillation in a Young Woman.JACC. Case reports · 2026Article
- New frontiers in porcine atrioventricular node decellularization: preserving extracellular matrix architecture for biological scaffolds.Frontiers in bioengineering and biotechnology · 2026Article
- Clockwise bundle branch re-entrant ventricular tachycardia in a teenage patient as the first manifestation of dilated cardiomyopathy associated with the p.Ile512Leu TNNI3k variant: a case report.European heart journal. Case reports · 2025Article
- Tnni3k regulates cardiomyopathy and cardiac conduction disease through Nfatc1 signaling.Genes & diseases · 2025Article
- [Dilated cardiomyopathy and conduction disorder due toArchivos de cardiologia de Mexico · 2025Article
- A New Mechanism of Supraventricular Tachycardia: Gene Mutation.Current cardiology reviews · 2025Review
- AFrontiers in genetics · 2025Article
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- Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review.International journal of molecular sciences · 2024Review
- Article
- Expression Levels of theInternational journal of molecular sciences · 2023Article
- Genetic Burden ofCirculation. Genomic and precision medicine · 2023Article
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2022Article
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.Journal of arrhythmia · 2022Article
- Whole-Exome Sequencing Identifies a Novel Variant (c.1538T > C) ofFrontiers in cardiovascular medicine · 2022Article
- A Novel Missense Mutation inGenes · 2021Article
- Functional testing for variant prioritization in a family with long QT syndrome.Molecular genetics and genomics : MGG · 2021Article
- The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment.International journal of molecular sciences · 2021Review
- A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.Scientific reports · 2021Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.
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