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Published on: March 12, 2013
Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac
Elisabeth M Lodder1, Brendon P Scicluna, Annalisa Milano
1Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Insights
Scientists identified Tnni3k as a gene influencing heart rhythm. This discovery sheds light on the genetic basis of atrio-ventricular conduction and may help understand sudden cardiac death risks.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Electrophysiology
Background:
- Atrio-ventricular conduction disease, marked by prolonged PR interval on ECG, is linked to Mendelian rhythm disorders and sudden cardiac death.
- PR interval prolongation predicts atrial fibrillation, a common arrhythmia, yet its genetic regulators are poorly understood.
- Previous studies mapped a quantitative trait locus (QTL) for PR interval duration in mice.
Purpose of the Study:
- To identify the specific gene responsible for the PR interval duration QTL in mice.
- To investigate the role of Tnni3k in regulating atrio-ventricular conduction.
Main Methods:
- Genome-wide transcriptional profiling of myocardial tissue from 109 F2 mice.
- Mapping of expression QTLs (eQTLs) and correlation analysis with PR interval duration.
- Genotype analysis and PR interval measurements in various inbred mouse strains, including genetically modified mice.
Main Results:
- Tnni3k was identified as the sole eQTL within the PR interval QTL region, exhibiting cardiac-specific expression and correlating with PR duration.
- Multiple Tnni3k haplotypes exist across mouse strains, with higher mRNA levels associated with longer PR intervals.
- Overexpression of Tnni3k in mice led to a prolonged PR interval.
Conclusions:
- Tnni3k plays a significant role in controlling the electrocardiographic PR interval.
- This finding provides the first evidence linking Tnni3k to atrio-ventricular conduction regulation.
- Tnni3k is a potential target for understanding and managing cardiac conduction disorders.
Abstract:
Atrio-ventricular conduction disease is a common feature in Mendelian rhythm disorders associated with sudden cardiac death and is characterized by prolongation of the PR interval on the surface electrocardiogram (ECG). Prolongation of the PR interval is also a strong predictor of atrial fibrillation, the most prevalent sustained cardiac arrhythmia. Despite the significant genetic component in PR duration variability, the genes regulating PR interval duration remain largely elusive. We here aimed to dissect the quantitative trait locus (QTL) for PR interval duration that we previously mapped in murine F2 progeny of a sensitized 129P2 and FVBN/J cross. To determine the underlying gene responsible for this QTL, genome-wide transcriptional profiling was carried out on myocardial tissue from 109 F2 mice. Expression QTLs (eQTLs) were mapped and the PR interval QTL was inspected for the co-incidence of eQTLs. We further determined the correlation of each of these transcripts to the PR interval. Tnni3k was the only eQTL, mapping to the PR-QTL, with an established abundant cardiac-specific expression pattern and a significant correlation to PR interval duration. Genotype inspection in various inbred mouse strains revealed the presence of at least three independent haplotypes at the Tnni3k locus. Measurement of PR interval duration and Tnni3k mRNA expression levels in six inbred lines identified a positive correlation between the level of Tnni3k mRNA and PR interval duration. Furthermore, in DBA/2J mice overexpressing hTNNI3K, and in DBA.AKR.hrtfm2 congenic mice, which harbor the AKR/J "high-Tnni3k expression" haplotype in the DBA/2J genetic background, PR interval duration was prolonged as compared to DBA/2J wild-type mice ("low-Tnni3k expression" haplotype). Our data provide the first evidence for a role of Tnni3k in controlling the electrocardiographic PR interval indicating a function of Tnni3k in atrio-ventricular conduction.
