Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients’ skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP’s role in normal and diseased skeletal muscle homeostasis.

中文翻译：

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MLIP 引起隐性肌病，伴有横纹肌溶解、肌痛和基线血清肌酸激酶升高

横纹肌需要维持细胞稳态以适应生理和代谢需求的增加。不这样做会导致横纹肌溶解症。与横纹肌溶解症相关的新遗传病的鉴定有助于阐明迄今为止未被认识的稳态机制。在这里，我们报告了来自不同种族背景的 6 个家庭中的 7 个个体，它们在 MLIP 中具有双等位基因变体，其编码肌肉核纤层蛋白 A/C 相互作用蛋白 MLIP。患者表现出一致的表型，其特征是轻度肌肉无力、运动引起的肌肉疼痛、对横纹肌溶解症发作的易感性不同以及血清肌酸激酶水平持续升高。预计双等位基因截断变体会导致 MLIP 的核定位信号中断。此外，在患者的骨骼肌中观察到主要 MLIP 同种型的总体 RNA 表达水平降低。总的来说，我们的数据增加了对横纹肌溶解症遗传景观的理解，现在将 MLIP 作为人类新的疾病基因包括在内，并巩固了 MLIP 在正常和患病骨骼肌稳态中的作用。