Dissection of a Quantitative Trait Locus for PR Interval Duration Identifies Tnni3k as a Novel Modulator of Cardiac Conduction

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 h TNNI3K , 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.

... Dissection of a Quantitative Trait Locus for PR Interval Duration Identifies Tnni3k as a Novel Modulator of Cardiac Conduction Tnni3k Is a Novel Modulator of Cardiac Conduction Lodder Elisabeth M. 1 Scicluna Brendon P. 1 Milano Annalisa 1 Sun Albert Y. 2 Tang Hao 3 Remme Carol Ann 1 Moerland Perry D. 4 Tanck Michael W. T. 4 Pitt Geoffrey S. 2 Marchuk Douglas A. 3 Bezzina Connie R. 1 * 1 Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center

... 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 h TNNI3K , 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. Author Summary Atrio-ventricular (AV) conduction disease (delay), characterized by prolongation of the PR interval on the surface electrocardiogram (ECG), is a common feature in Mendelian rhythm disorders and is associated with sudden cardiac death. Prolongation of the PR interval is also a strong predictor of atrial fibrillation (AF), the most

... Tnni3k as prime candidate for the modulation of the PR interval duration and suggest a new role for this gene, in the modulation of atrio-ventricular conduction. This study was funded by a Netherlands Heart Foundation Established Investigator Fellowship to CRB (NHS 2005T024, www.hartstichting.nl/ ) and the Inter-University Cardiology Institute of the Netherlands (ICIN project 06401, http://www.icin.nl/ ). The funders had no role in study design, data collection and analysis, decision to publish, or

... PR interval QTL. Of the thus found 16 eQTLs only Tnni3k expression levels both correlated to the PR interval and had a high cardiac specific expression. We integrated genome-wide transcriptional profiles of myocardial tissue with genotypic data in F2 progeny from the 129P2- Scn5a 1798insD/+ FVBN/J- Scn5a 1798insD/+ cross to uncover eQTLs that overlapped with the chromosome 3 PR interval QTL. Of these eQTLs, only the transcript for Tnni3k both correlated to the PR interval and was highly and specifically expressed in heart; Tnni3k was thus identified as a very strong candidate for the effect. The role of Tnni3k was subsequently validated in silico using phenotypic data from the mouse phenome database [12] . Further validation was performed by testing the correlation of Tnni3k expression level with PR interval in 6 inbred mouse strains harboring 3 independent haplotypes at the Tnni3k genomic locus. Finally, the role of Tnni3k in modulation of the PR interval was validated in vivo in (i

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Gene: TNNI3K - TNNI3 interacting kinase - (NCBI)

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