Dilated cardiomyopathy in the nmd mouse:: transgenic rescue and QTLs that improve cardiac function and survival
Dilated cardiomyopathy in the nmd mouse:: transgenic rescue and QTLs that improve cardiac function and survival
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DOI：
10.1093/hmg/ddi349
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Cox, GA
中科院分区：
文献类型：
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作者：
Maddatu, TP;Garvey, SM;Cox, GA
免疫球蛋白Mu结合蛋白-2（Ighmbp2）基因突变导致神经肌肉变性（nmd）小鼠的运动神经元疾病和扩张型心肌病（DCM）以及人类的脊髓性肌萎缩伴呼吸窘迫（SMARD 1）。为了研究IGHMBP2在DCM发病机制中的作用，我们在小鼠肌联蛋白启动子的控制下产生了特异性地在肌细胞中表达全长Ighmbp2 cDNA的转基因小鼠。这种组织特异性转基因通过预防原发性DCM将nmd小鼠的寿命延长了8倍，并通过ECG，超声心动图和血浆肌酸激酶-MB测量显示出完全的功能校正。在肌细胞和神经元中表达Ighmbp2的双转基因nmd小鼠显示DCM和运动神经元疾病的校正，导致基本上野生型的外观。此外，进行数量性状基因座（QTL）分析，以确定遗传修饰基因座负责保存心脏功能和显着延迟心肌病的发作在CAST/EiJ回交人口。在9、10和16号染色体上鉴定了三种主要的CAST衍生的nmd心脏修饰剂，其占遗传变异的26%以上，并且继续抑制心肌病的恶化，否则导致早期死亡，作为早期B6.CAST同源物。总的来说，我们的研究结果证实了IGHMBP2在心肌细胞维持和存活中的组织特异性需求，并描述了遗传修饰剂，其可以通过心脏功能适应和身体重塑来改变DCM的过程，以响应负荷和呼吸需求的变化。
Mutations in the immunoglobulin mu binding protein-2 (Ighmbp2) gene cause motor neuron disease and dilated cardiomyopathy (DCM) in the neuromuscular degeneration (nmd) mouse and spinal muscular atrophy with respiratory distress (SMARD1) in humans. To investigate the role of IGHMBP2 in the pathogenesis of DCM, we generated transgenic mice expressing the full-length Ighmbp2 cDNA specifically in myocytes under the control of the mouse titin promoter. This tissue-specific transgene increased the lifespan of nmd mice up to 8-fold by preventing primary DCM and showed complete functional correction as measured by ECG, echocardiography and plasma creatine kinase-MB. Double-transgenic nmd mice expressing Ighmbp2 both in myocytes and in neurons display correction of both DCM and motor neuron disease, resulting in an essentially wild-type appearance. Additionally, quantitative trait locus (QTL) analysis was undertaken to identify genetic modifier loci responsible for the preservation of cardiac function and a marked delay in the onset of cardiomyopathy in a CAST/EiJ backcross population. Three major CAST-derived cardiac modifiers of nmd were identified on chromosomes 9, 10 and 16, which account for over 26% of the genetic variance and that continue to suppress the exacerbation of cardiomyopathy, otherwise resulting in early death, as incipient B6.CAST congenics. Overall, our results verify the tissue-specific requirement for IGHMBP2 in cardiomyocyte maintenance and survival and describe genetic modifiers that can alter the course of DCM through cardiac functional adaptation and physical remodeling in response to changes in load and respiratory demand.