Animal models for genetic neuromuscular diseases
Animal models for genetic neuromuscular diseases
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DOI：
10.1007/s12031-007-9023-9
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发表时间：
2008-03-01
影响因子：
3.1
通讯作者：
Yamamoto, Lydia U.
中科院分区：
文献类型：
--
作者：
Vainzof, Mariz;Ayub-Guerrieri, Danielle;Yamamoto, Lydia U.
神经肌肉疾病是一组异质性遗传疾病，由编码肌纤维膜、肌节和胞质肌肉蛋白的基因突变引起。这些蛋白质的功能缺陷或丧失导致不同程度的运动能力进行性丧失。已经在自然界中鉴定或在实验室中产生了几种动物模型，其表现出在神经肌肉疾病中观察到的表型。这些模型通常呈现在人类患者中观察到的生理改变，并且可以用作遗传、临床和组织病理学研究的重要工具。mdx小鼠是Duchenne肌营养不良症（DMD）最广泛使用的动物模型。虽然这是一个很好的遗传和生化模型，在肌肉中的蛋白质肌营养不良蛋白的总缺陷，这种小鼠是没有用的临床试验，因为它非常温和的表型。犬金毛猎犬MD模型由于其较大的尺寸和显著的肌肉无力而代表了临床上更相似的DMD模型。常染色体隐性肢带型MD模型包括SJL/J小鼠，其发展了由Dysferlin基因突变引起的自发性肌病，是LGMD 2B的模型。对于人肌聚糖病（SG），BIO14.6仓鼠是δ-SG缺乏症的自发动物模型，而一些SG蛋白缺乏症的犬模型也已确定。最近，利用胚胎干细胞中的同源重组技术，已经开发了几种小鼠模型，其中四个SG基因中的每一个都具有无效突变。所有肌聚糖缺失动物均表现出不同严重程度的进行性肌营养不良症，并具有肌聚糖亚复合物的其他成员和肌营养不良蛋白-糖蛋白复合物的其他组分的表达显著继发性降低的特性。先天性MD的小鼠模型包括dy/dy（肌营养不良）小鼠和等位基因突变dy（2 J）/dy（2 J）小鼠，两者均呈现肌肉中α 2-层粘连蛋白的显著减少和严重表型。肌营养不良小鼠（Large（myd））在糖基转移酶Large中存在突变，导致α-DG的糖基化改变，也导致严重的表型。肌肉蛋白质的其他信息模型包括肌肉生长抑制素基因敲除小鼠，它证明了这种蛋白质是肌肉生长的负调节因子。此外，由猪RYR 1基因突变引起的猪应激综合征有助于定位导致人类恶性高热症和中央核心肌病的基因。遗传性疾病的动物模型的研究，尽管存在的差异，在一些表型，可以提供重要的线索，了解这些疾病的发病机制，也是非常有价值的测试策略的治疗方法。
The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for delta-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy(2J)/dy(2J) mouse, both presenting significant reduction of alpha 2-laminin in the muscle and a severe phenotype. The myodystrophy mouse (Large(myd)) harbors a mutation in the glycosyltransferase Large, which leads to altered glycosylation of alpha-DG, and also a severe phenotype. Other informative models for muscle proteins include the knockout mouse for myostatin, which demonstrated that this protein is a negative regulator of muscle growth. Additionally, the stress syndrome in pigs, caused by mutations in the porcine RYR1 gene, helped to localize the gene causing malignant hypertermia and Central Core myopathy in humans. The study of animal models for genetic diseases, in spite of the existence of differences in some phenotypes, can provide important clues to the understanding of the pathogenesis of these disorders and are also very valuable for testing strategies for therapeutic approaches.