Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene.
Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene.
复制标题
通过靶向破坏 Six5 基因来表征小鼠心脏传导系统异常。
DOI：
10.1023/a:1020881520353
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Berul,CharlesI
中科院分区：
文献类型：
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作者：
Wakimoto,Hiroko;Maguire,ColinT;Sherwood,MeganC;Vargas,MarcelM;Sarkar,ParthaS;Han,Jennifer;Reddy,Sita;Berul,CharlesI
强直性肌营养不良（Myotonic dystrophy，DM）是一种常染色体显性遗传性多系统疾病，由位于染色体19 q13上的强直性肌营养不良蛋白激酶（Myotonic dystrophy protein kinase，DMPK）基因3′端非翻译区的CTG三核苷酸重复序列扩增引起。糖尿病的心脏受累包括传导异常和功能缺陷。DM病理生理学的分子机制的三个假设是：第一，强直性肌营养不良蛋白激酶（DMPK）的部分损失;第二，相邻同源结构域编码基因Six 5（或DMAHP）的转录减少;第三，RNA的转显性效应和与扩展的CUG重复表达相关的剪接调节。然而，其确切的发病机制仍不清楚。我们以前报道过DMPK的小鼠同源物Dm 15的剂量与心脏传导异常密切相关。为了进一步区分糖尿病心脏表型的分子机制，在本研究中，我们对Six 5基因靶向破坏的小鼠的心脏传导结果进行了表征。本研究采用在体电生理技术、超声心动图、心率变异性和运动耐量试验，对65只杂合子小鼠（成年和幼年）及其同龄野生型小鼠进行了研究。未检测到PR延长，但在成年Six 5杂合子小鼠中，QRS持续时间延长和希氏束下传导延迟显著。通过超声心动图，左心室（LV）舒张末期的尺寸在成年Six 5杂合子小鼠扩大，但无论是分数缩短或LV壁厚度显示出显着差异。Six 5缺失可能部分导致强直性肌营养不良的传导异常，特别是希氏束下传导延迟，这是DM患者成人发作心脏传导异常的初始表型之一。
Myotonic dystrophy (DM) is an autosomal dominant multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3′ untranslated region of the myotonic dystrophy protein kinase gene (DMPK) on chromosome 19q13. Cardiac involvement in DM includes conduction abnormalities and functional deficits. Three hypotheses of molecular mechanisms for DM pathophysiology are; first, partial loss of myotonic dystrophy protein kinase (DMPK); second, decreased transcription of a neighboring homeodomain-encoding gene, Six5 (or DMAHP), and third, transdominant effects of the RNA and regulation of splicing associated with expression of expanded CUG repeats. However, the precise pathogenetic mechanism remains unresolved. We previously reported that dosage of Dm15, the mouse homologue of DMPK, strongly associates with the cardiac conduction abnormalities. For further distinction of the molecular mechanisms underlying the cardiac phenotype of DM, in the present study, we characterized the cardiac conduction findings of mice with targeted disruption of Six5 gene. Six5 heterozygous mice (adult and young) and their age matched wild type littermates were studied usingin vivoelectrophysiologic techniques, echocardiography, heart rate variability and exercise tolerance testing. No PR prolongation was detected, however, prolonged QRS duration and delayed infraHisian conduction were significant in adult Six5 heterozygous mice. By echocardiography, left ventricular (LV) end-diastolic dimension was enlarged in adult Six5 heterozygous mice, although neither fractioning shortening nor LV wall thickness showed significant differences. Six5 loss may partly contribute to conduction abnormalities in myotonic dystrophy, particularly infraHisian conduction delay, one of the initial phenotypes of adult-onset cardiac conduction abnormalities in DM patients.