School of Biochemistry, University of Bristol, Bristol, UK.
Istituto di Chimica del Riconoscimento Molecolare - CNR c/o Università Cattolica del Sacro Cuore, Roma, Italy.
J Cell Mol Med. 2019 May;23(5):3058-3062. doi: 10.1111/jcmm.14218. Epub 2019 Mar 5.
Dystroglycan is a major non-integrin adhesion complex that connects the cytoskeleton to the surrounding basement membranes, thus providing stability to skeletal muscle. In Vertebrates, hypoglycosylation of α-dystroglycan has been strongly linked to muscular dystrophy phenotypes, some of which also show variable degrees of cognitive impairments, collectively termed dystroglycanopathies. Only a small number of mutations in the dystroglycan gene, leading to the so called primary dystroglycanopathies, has been described so far, as opposed to the ever-growing number of identified secondary or tertiary dystroglycanopathies (caused by genetic abnormalities in glycosyltransferases or in enzymes involved in the synthesis of the carbohydrate building blocks). The few mutations found within the autonomous N-terminal domain of α-dystroglycan seem to destabilise it to different degrees, without influencing the overall folding and targeting of the dystroglycan complex. On the contrary other mutations, some located at the α/β interface of the dystroglycan complex, seem to be able to interfere with its maturation, thus compromising its stability and eventually leading to the intracellular engulfment and/or partial or even total degradation of the dystroglycan uncleaved precursor.
肌聚糖蛋白是一种主要的非整联蛋白黏附复合物，它将细胞骨架与周围的基底膜连接起来，从而为骨骼肌提供稳定性。在脊椎动物中，α-肌聚糖蛋白的低聚糖化为肌肉营养不良表型提供了强有力的联系，其中一些表型还表现出不同程度的认知障碍，统称为肌聚糖蛋白病。迄今为止，只有少数肌聚糖蛋白基因突变被描述为所谓的原发性肌聚糖蛋白病，而越来越多的继发性或三级肌聚糖蛋白病（由糖基转移酶或参与碳水化合物构建块合成的酶中的遗传异常引起）被发现。在 α-肌聚糖蛋白自主 N 端结构域内发现的少数突变似乎在不同程度上使其不稳定，而不影响肌聚糖蛋白复合物的整体折叠和靶向。相反，其他突变，一些位于肌聚糖蛋白复合物的 α/β 界面，似乎能够干扰其成熟，从而损害其稳定性，并最终导致未切割前体的细胞内吞噬和/或部分甚至完全降解。
