Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy.
Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy.
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DOI：
10.1093/hmg/ddn387
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Toda T
中科院分区：
文献类型：
--
作者：
Kanagawa M;Nishimoto A;Chiyonobu T;Takeda S;Miyagoe-Suzuki Y;Wang F;Fujikake N;Taniguchi M;Lu Z;Tachikawa M;Nagai Y;Tashiro F;Miyazaki J;Tajima Y;Takeda S;Endo T;Kobayashi K;Campbell KP;Toda T
α-肌营养不良蛋白聚糖的低糖基化和层粘连蛋白结合活性降低是肌营养不良蛋白聚糖病的共同特征，肌营养不良蛋白聚糖病是一组先天性和肢带型肌营养不良症。福山型先天性肌营养不良症（FCMD），由fukamyosine基因突变引起，是一种严重的肌营养不良症。几乎所有的FCMD病例都可见股骨柄后插入。为了更好地理解肌营养不良聚糖病的分子发病机制并探索治疗策略，我们产生了在小鼠fuklastin直系同源物中携带逆转录酶插入的敲入小鼠。敲入小鼠表现出低糖基化的α-肌营养不良聚糖;然而，未观察到肌营养不良的体征。更灵敏的方法检测到少量完整的α-肌营养不良蛋白聚糖，固相测定确定层粘连蛋白结合水平为正常水平的50%左右。相反，在营养不良的Largemyd小鼠中检测不到完整的α-肌营养不良蛋白聚糖，并且层粘连蛋白结合活性显著降低。这些数据表明，少量完整的α-肌营养不良聚糖足以维持基因敲入小鼠中的肌细胞完整性，表明肌营养不良聚糖病的治疗可能不需要完全恢复糖基化。为了检查糖基化缺陷是否可以在体内恢复，我们进行了小鼠基因转移实验。将fuklavin转移到基因敲入小鼠中恢复了α-肌营养不良聚糖的糖基化。此外，LARGE的转移在基因敲入小鼠和POMGnT 1突变小鼠中产生了层粘连蛋白结合形式的α-肌营养不良聚糖，这是另一种肌营养不良聚糖病模型。总体而言，这些数据表明，通过替换或增强糖基化相关基因，即使α-肌营养不良聚糖糖基化和层粘连蛋白结合活性部分恢复，也可能有效阻止肌营养不良聚糖病进展，从而提供治疗益处。
Hypoglycosylation and reduced laminin-binding activity of α-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. Fukuyama-type congenital muscular dystrophy (FCMD), caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. A retrotransposal insertion in fukutin is seen in almost all cases of FCMD. To better understand the molecular pathogenesis of dystroglycanopathies and to explore therapeutic strategies, we generated knock-in mice carrying the retrotransposal insertion in the mouse fukutin ortholog. Knock-in mice exhibited hypoglycosylated α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be ∼50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Largemyd mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. To examine whether glycosylation defects can be restored in vivo, we performed mouse gene transfer experiments. Transfer of fukutin into knock-in mice restored glycosylation of α-dystroglycan. In addition, transfer of LARGE produced laminin-binding forms of α-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse, which is another model of dystroglycanopathy. Overall, these data suggest that even partial restoration of α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
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影响因子：
3.5
作者：
Brockington, M;Yuva, Y;Muntoni, F
通讯作者：
Muntoni, F
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4
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Yamamura, KI
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作者：
Dinçer, P;Balci, B;Topaloglu, H
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Topaloglu, H