Maddatu Terry P, Garvey Sean M, Schroeder David G, Zhang Wiedong, Kim Soh-Yule, Nicholson Anthony I, Davis Crystal J, Cox Gregory A
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Hum Mol Genet. 2005 Nov 1;14(21):3179-89. doi: 10.1093/hmg/ddi349. Epub 2005 Sep 20.
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.
免疫球蛋白μ结合蛋白2（Ighmbp2）基因突变可导致神经肌肉变性（nmd）小鼠出现运动神经元疾病和扩张型心肌病（DCM），在人类中则导致伴有呼吸窘迫的脊髓性肌萎缩（SMARD1）。为了研究IGHMBP2在DCM发病机制中的作用，我们构建了在小鼠肌联蛋白启动子控制下，在心肌细胞中特异性表达全长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使nmd小鼠的寿命延长了8倍，并且通过心电图、超声心动图和血浆肌酸激酶-MB检测显示完全的功能纠正。在心肌细胞和神经元中均表达Ighmbp2的双转基因nmd小鼠，其DCM和运动神经元疾病均得到纠正，表现出基本的野生型外观。此外，进行了数量性状基因座（QTL）分析，以确定在CAST/EiJ回交群体中负责维持心脏功能和显著延迟心肌病发病的遗传修饰基因座。在9号、10号和16号染色体上鉴定出三个主要的源自CAST的nmd心脏修饰基因，它们占遗传变异的26%以上，并且作为初始的B6.CAST同源基因，继续抑制心肌病的恶化，否则会导致早期死亡。总体而言，我们的结果证实了IGHMBP2在心肌细胞维持和存活中的组织特异性需求，并描述了通过心脏功能适应和物理重塑以应对负荷和呼吸需求变化从而改变DCM病程的遗传修饰基因。
