The limb-girdle muscular dystrophies (LGMDs) are a genetically pleiomorphic class of inherited muscle diseases that are known to share phenotypic features. Selected LGMD genetic subtypes have been studied extensively in affected humans and various animal models. In some cases, these investigations have led to human clinical trials of potential disease-modifying therapies, including gene replacement strategies for individual subtypes using adeno-associated virus (AAV) vectors. The cellular localizations of most proteins associated with LGMD have been determined. However, the functions of these proteins are less uniformly characterized, thus limiting our knowledge of potential common disease mechanisms across subtype boundaries. Correspondingly, broad therapeutic strategies that could each target multiple LGMD subtypes remain less developed. We believe that three major “functional clusters” of subcellular activities relevant to LGMD merit further investigation. The best known of these is the glycosylation modifications associated with the dystroglycan complex. The other two, mechanical signaling and mitochondrial dysfunction, have been studied less systematically but are just as promising with respect to the identification of significant mechanistic subgroups of LGMD. A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.

中文翻译：

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结合的纽带：肢带型肌营养不良症中的功能群。

肢带型肌营养不良症 (LGMDs) 是一种遗传性多形性遗传性肌肉疾病，已知具有共同的表型特征。已在受影响的人类和各种动物模型中广泛研究了选定的 LGMD 遗传亚型。在某些情况下，这些研究已导致对潜在的疾病修饰疗法进行人体临床试验，包括使用腺相关病毒 (AAV) 载体对单个亚型进行基因置换策略。大多数与 LGMD 相关的蛋白质的细胞定位已经确定。然而，这些蛋白质的功能不太统一，因此限制了我们对跨亚型边界的潜在常见疾病机制的了解。相应地，可以针对多种 LGMD 亚型的广泛治疗策略仍然欠发达。我们认为与 LGMD 相关的亚细胞活动的三个主要“功能群”值得进一步研究。其中最著名的是与肌营养不良聚糖复合物相关的糖基化修饰。另外两个，机械信号传导和线粒体功能障碍，研究较少，但在识别 LGMD 的重要机械亚组方面同样有希望。对这些疾病途径的更深入了解可以产生新一代的精准疗法，每一种疗法都有望治疗比单一亚型更广泛的 LGMD 患者，从而扩大可能为这种复杂的一系列疾病开发的分子药物的范围。肌肉萎缩症。