The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

肌球蛋白指导的伴侣UNC-45B对于从秀丽隐杆线虫到人类的肌节组织和肌肉功能至关重要。UNC-45B在肌肉疾病中的病理影响仍然难以捉摸。我们报告UNC45B中有十个具有双等位基因变异的个体，这些个体表现出儿童期发作的进行性肌无力。我们确定了一个普通的UNC45B变体，它可以充当复杂的亚体剪接变体。纯化的UNC-45B突变体显示出折叠和溶解度的变化。原位定位研究进一步证明，突变型UNC-45B在肌肉中的表达降低，并伴有异常的定位，即从肌小节的A波段向Z盘转移。这些观察的生理意义在秀丽隐杆线虫通过保守的UNC-45错义变体的转基因表达，显示出肌球蛋白结合能力受损（一种）和肌肉功能受损（三种）。在一起，我们的结果表明，UNC-45B损伤表现为伴有进行性肌肉病理的伴侣病，这发现了UNC-45B在肌原纤维组织中的先前未知的保守作用。