A novel β-myosin heavy chain gene mutation, p.Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model
A novel β-myosin heavy chain gene mutation, p.Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model
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DOI：
10.1042/cs20070179
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发表时间：
2008-03-01
期刊：
影响因子：
6
通讯作者：
Asano, Masahide
中科院分区：
文献类型：
--
作者：
Kaneda, Tomoya;Naruse, Chie;Asano, Masahide
肌球蛋白重链是一种肌节蛋白，它的突变导致肥厚型和扩张型心肌病。然而，β-MHC基因的不同突变导致两种心肌病的机制仍不清楚。在目前的研究中，我们报道了在一例孤立的LVNC患者中发现的一种新的β-MHC突变[LV(左心室)致密化不全]，并报告了携带相同突变的小鼠突变模型的表型。为了找出突变的原因，我们搜索了99名无关的扩张型心肌病先证者和5名孤立性LVNC先证者的基因组突变，并在一名13岁的孤立性LVNC女孩的βMHC中发现了p.Met531Arg突变。接下来，我们产生了六个转基因小鼠系，携带p.Met532Arg突变的αMHC基因，这与人类αMHC中的p.Met531Arg突变相同。其中，两个突变型aMHC基因表达较强的品系被选作进一步研究。虽然它们没有表现出LVNC的特征，但大约。每个品系的转基因小鼠在2-3个月龄时分别有50%和70%的转基因小鼠表现出左心室肥厚(LV Hypertro.phy)。此外，LVD(LV扩张术)在大约到18个月龄时，25%的转基因小鼠表现出左室壁厚度的双相变化。本研究支持LVH和LVD可能涉及共同机制的观点。所建立的新的小鼠模型可以为了解人类心脏扩张的病理过程和病因学提供重要信息。
Mutations in the beta MHC (beta-myosin heavy chain), a sarcomeric protein are responsible for hypertrophic and dilated cardiomyopathy. However, the mechanisms whereby distinct mutations in the beta MHC gene cause two kinds of cardiomyopathy are still unclear. In the present study we report a novel beta MHC mutation found in a patient with isolated LVNC [LV (left ventricular) non-compaction] and the phenotype of a mouse mutant model carrying the same mutation. To find the mutation responsible, we searched for genomic mutations in 99 unrelated probands with dilated cardiomyopathy and five probands with isolated LVNC, and identified a p.Met531Arg mutation in beta MHC in a 13-year-old girl with isolated LVNC. Next, we generated six lines of transgenic mice carrying a p.Met532Arg mutant alpha MHC gene, which was identical with the p.Met531Arg mutation in the human alpha MHC. Among these, two lines with strong expression of the mutant aMHC gene were chosen for further studies. Although they did not exhibit the features characteristic of LVNC, approx. 50% and 70% of transgenic mice in each line displayed LVH (LV hypertro.phy) by 2-3 months of age. Furthermore, LVD (LV dilation) developed in approx. 25% of transgenic mice by 18 months of age, demonstrating biphasic changes in LV wall thickness. The present study supports the idea that common mechanisms may be involved in LVH and LVD. The novel mouse model generated can provide important information for the understanding of the pathological processes and aetiology of cardiac dilation in humans.