Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies
Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies
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DOI：
10.1038/nature00837
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发表时间：
2002-07-25
期刊：
影响因子：
64.8
通讯作者：
Campbell, KP
中科院分区：
文献类型：
--
作者：
Michele, DE;Barresi, R;Campbell, KP
肌-眼-脑疾病（MEB）和福山先天性肌营养不良症（FCMD）是先天性肌营养不良症伴相关的相似脑畸形（1，2）。FCMD基因，fukaline，与条纹样糖基转移酶具有一定的同源性，MEB基因，POMGnT 1，似乎是一种新的糖基转移酶（3，4）。在这里，我们表明，在MEB和FCMD患者中，α-肌营养不良蛋白聚糖在肌膜上表达，但在疾病中类似的低糖基化直接消除了肌营养不良蛋白聚糖与配体层粘连蛋白、neurexin和聚集蛋白的结合活性。我们表明，这种翻译后的生化和功能破坏的α-肌营养不良蛋白聚糖是重演的肌肉和中枢神经系统的突变型肌营养不良症（myd）小鼠。我们证明，myd小鼠大脑皮质，小脑和海马的神经元迁移异常，并显示基底层破坏。此外，myd小鼠揭示肌营养不良蛋白聚糖通过其与细胞外基质蛋白的相互作用将蛋白质靶向到脑中的功能位点。这些结果表明，至少有三个不同的哺乳动物基因的功能，在一个收敛的翻译后加工途径在肌营养不良蛋白聚糖的生物合成，和异常的肌营养不良蛋白聚糖配体相互作用的基础上的致病机制与脑异常的肌营养不良症。
Muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations(1,2). The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase(3,4). Here we show, in both MEB and FCMD patients, that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.