Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac conduction.
Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac conduction.
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DOI：
10.1371/journal.pgen.1003113
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Bezzina CR
中科院分区：
文献类型：
--
作者：
Lodder EM;Scicluna BP;Milano A;Sun AY;Tang H;Remme CA;Moerland PD;Tanck MW;Pitt GS;Marchuk DA;Bezzina CR
房室传导疾病是与心源性猝死相关的孟德尔节律障碍的共同特征，其特征是表面心电图（ECG） PR间期延长。PR间期的延长也是房颤的一个强有力的预测因子，房颤是最常见的持续性心律失常。尽管PR间隔时间的变异具有重要的遗传成分，但调节PR间隔时间的基因在很大程度上仍然难以捉摸。我们在这里的目的是解剖我们之前在129P2和FVBN/J杂交的小鼠F2后代中定位的PR间隔时间的数量性状位点（QTL）。为了确定该QTL的潜在基因，对109只F2小鼠的心肌组织进行了全基因组转录谱分析。绘制表达QTL （eqtl）图谱，并检测PR区间QTL是否与eqtl共发。我们进一步确定了这些转录本与PR区间的相关性。Tnni3k是唯一映射到PR- qtl的eQTL，具有丰富的心脏特异性表达模式，与PR间期持续时间显著相关。不同近交系小鼠的基因型检测显示，在Tnni3k位点存在至少三个独立的单倍型。通过对6个自交系PR间期持续时间和Tnni3k mRNA表达水平的测定，发现Tnni3k mRNA水平与PR间期持续时间呈正相关。此外，过表达hTNNI3K的DBA/2J小鼠和过表达hTNNI3K的DBA/2J小鼠。hrtfm2基因小鼠在DBA/2J遗传背景下具有AKR/J“高表达tnni3k”单倍型，与DBA/2J野生型小鼠（“低表达tnni3k”单倍型）相比，PR间隔时间延长。我们的数据为Tnni3k在控制心电图PR间期中的作用提供了第一个证据，表明Tnni3k在房室传导中的作用。房室（AV）传导疾病（延迟）以表面心电图（ECG）上PR间期延长为特征，是孟德尔节律障碍的共同特征，并与心源性猝死相关。PR间期的延长也是房颤（AF）的一个强有力的预测因子，房颤是最常见的持续性心律失常。尽管PR间隔的可变性有很大的遗传成分，但致病基因在很大程度上仍然难以捉摸。由于广泛的遗传异质性和难以控制的环境，在人类群体中鉴定这些遗传因素一直很困难。我们利用同质遗传背景和控制环境的自交系实验室小鼠品系来检测PR间隔的遗传修饰。我们确定Tnni3k是调节PR间期持续时间的主要候选基因，并提出该基因在调节房室传导中的新作用。
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. 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 common sustained cardiac arrhythmia. Although there is a substantial heritable component to the variability of the PR interval, the causative genes remain largely elusive. The identification of these genetic factors in the human population has been difficult owing to wide genetic heterogeneity and an uncontainable environment. We here exploited the homogeneous genetic background and controlled environment of inbred laboratory mouse strains to detect a genetic modifier of the PR interval. We identify 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.
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影响因子：
20.1
作者：
Remme, Carol Ann;Scicluna, Brendon P.;Bezzina, Connie R.
通讯作者：
Bezzina, Connie R.
DOI：
10.1111/j.1540-8167.2007.01073.x
发表时间：
2008-04-01
影响因子：
2.7
作者：
Scicluna, Brendon P.;Wilde, Arthur W.;Bezzina, Connie R.
通讯作者：
Bezzina, Connie R.
影响因子：
30.8
作者：
通讯作者：
--
综合基因组方法暗示骨甘氨酸（OGN）在左心室肿块的调节中。
影响因子：
30.8
作者：
Petretto, Enrico;Sarwar, Rizwan;Grieve, Ian;Lu, Han;Kumaran, Mande K.;Muckett, Phillip J.;Mangion, Jonathan;Schroen, Blanche;Benson, Matthew;Punjabi, Prakash P.;Prasad, Sanjay K.;Pennell, Dudley J.;Kiesewetter, Chris;Tasheva, Elena S.;Corpuz, Lolita M.;Webb, Megan D.;Conrad, Gary W.;Kurtz, Theodore W.;Kren, Vladimir;Fischer, Judith;Hubner, Norbert;Pinto, Yigal M.;Pravenec, Michal;Aitman, Timothy J.;Cook, Stuart A.
通讯作者：
Cook, Stuart A.
影响因子：
1.3
作者：
HAVLIK, RJ;GARRISON, RJ;FEINLEIB, M
通讯作者：
FEINLEIB, M