JCI：新型小鼠模型为肌肉萎缩症治疗提供思路

肌肉萎缩症（muscular dystrophy）是一种比较复杂的遗传性疾病，遗传突变可以改变几种不同的蛋白质的功能，而这些蛋白质可以形成一种复合物，这种复合物却是连接肌肉细胞和细胞外基质（ECM）之间的“结构大桥”。在病人中，这种遗传突变所引发的效应非常广泛，为了开发出新型的疗法，研究者需要特定的动物模型来精确在其体内表现出人类疾病的状况和疾病发病过程。

近日，刊登在国际杂志the Journal of Clinical Investigation上的一篇研究报告中，来自美国爱荷华大学的研究者开发出了一种肌营养不良症的小鼠模型（Fukuyama's muscular dystrophy），利用此模型，研究者可以精确展现人类患肌营养不良症的病程以及病例表现。

在小鼠胚胎发育期间，通过多点移除基因fukutin，研究者就能够确定fukutin可以中断肌营养不良蛋白的修饰作用，而这种肌营养不良蛋白可以抑制小鼠肌肉细胞吸附到ECM上。

早期发育阶段破坏该基因可以导致小鼠的疾病加剧，这也就解释了fukutin基因对于肌肉成熟的重要性。在胚胎发育晚期阶段破坏该基因反而使得小鼠的病症可以减轻。在研究中，研究者揭示了这种新型疾病模型的应用价值以及其潜在的治疗肌肉萎缩症的新型疗法。

编译自：New Model of Muscular Dystrophy Provides Insight Into Disease Development

doi:10.1172/JCI63004
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Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Aaron M. Beedle1,2, Amy J. Turner1, Yoshiaki Saito1, John D. Lueck1, Steven J. Foltz2, Marisa J. Fortunato2, Patricia M. Nienaber1 and Kevin P. Campbell1

Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty-week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.