TANGO2 binds crystallin alpha B and its loss causes desminopathy

Mutations in the TANGO2 gene cause an autosomal recessive disorder characterised by developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias along with severe metabolic crises. Although TANGO2 mutations result in a well characterised disease pathology, the function of TANGO2 is still unknown. To investigate the function of TANGO2, we knocked out the TANGO2 gene in human cells and mice. We identify that loss of TANGO2 impairs intermediate filament structure, resulting in fragmented mitochondrial networks and formation of cup-like mitochondria. In mice loss of TANGO2 caused heart defects, reduced muscle function and hypoglycemia that were caused by remodelling of intermediate filaments, resulting in changes in the mitochondrial and cytoplasmic proteomes and glycosylation. We identify that TANGO2 binds the small heat shock protein crystallin alpha B (CRYAB) to prevent the aggregation of the intermediate filament desmin and in the absence of TANGO2, mice develop desminopathy, which is consistent with features found in patients carrying mutations either in desmin or CRYAB. Overall design: Total RNA differential gene expression changes between TANGO2 knockout and wild type CAL51 cells grown under glucose and galactose.

TANGO2基因的突变可引发常染色体隐性遗传病（autosomal recessive disorder），该病以发育迟缓、应激诱导的间歇性横纹肌溶解症、心律失常及严重代谢危象为特征。尽管TANGO2突变所致的疾病病理已得到充分阐明，但TANGO2的具体生物学功能仍未明确。为探究TANGO2的功能，我们分别在人类细胞与小鼠体内敲除了TANGO2基因。研究发现，TANGO2缺失会损害中间丝（intermediate filament）结构，导致线粒体网络碎片化并形成杯状线粒体。在小鼠模型中，TANGO2缺失可引发心脏缺陷、肌肉功能减退与低血糖症，上述表型由中间丝重塑所介导，进而引发线粒体与细胞质蛋白质组（proteome）及糖基化（glycosylation）的改变。我们还发现，TANGO2可结合小型热休克蛋白αB晶状体蛋白（CRYAB），以此阻止中间丝结蛋白（desmin）的聚集；而在TANGO2缺失的小鼠中，会出现结蛋白病（desminopathy），这与结蛋白或CRYAB突变患者的临床表型一致。整体实验设计：比较葡萄糖与半乳糖培养条件下，TANGO2基因敲除型与野生型CAL51细胞的总RNA差异基因表达变化。