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 male mice, loss of TANGO2 caused heart defects, reduced muscle function and glucose intolerance by remodelling of intermediate filaments, which altered the mitochondrial and cytoplasmic proteomes, N-glycosylation and nucleocytoplasmic O-GlcNAcylation. 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 in either desmin or CRYAB.

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Publication Details

Journal
Nature Communications
Published
2025-06-06
DOI
https://doi.org/10.1038/s41467-025-60563-1
Citations
2
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
2.78

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article

TANGO2 binds crystallin alpha B and its loss causes desminopathy

Stefan J. Siira, Tze‐Kiong Er, Shanti Balasubramaniam, Danielle L. Rudler et al.
2 citations
Nature Communications
Cardiomyopathy and Myosin Studies
2.78
article

TANGO2 binds crystallin alpha B and its loss causes desminopathy

Stefan J. Siira, Tze‐Kiong Er, Shanti Balasubramaniam, Danielle L. Rudler, Kara L. Perks, Livia C. Hool, Judith A. Ermer, Blake Payne, Tim McCubbin, Laetitia A. Hughes, Nicolle H. Packer, Aleksandra Filipovska, Maike Stentenbach, Oliver Rackham, Edward S. X. Moh, Benjamin Scott Padman, A Chopin, Samuel V. Fagan, J.H. Hendry, Joel A. Eliades
article en
2 citations

Abstract

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 male mice, loss of TANGO2 caused heart defects, reduced muscle function and glucose intolerance by remodelling of intermediate filaments, which altered the mitochondrial and cytoplasmic proteomes, N-glycosylation and nucleocytoplasmic O-GlcNAcylation. 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 in either desmin or CRYAB.

Nature CommunicationsVol. 16(1)
The University of Sydney (AU), The University of Queensland (AU), The University of Western Australia (AU), Victor Chang Cardiac Research Institute (AU), Curtin University (AU), Discovery Institute (US), Princess Margaret Hospital for Children (AU), Australian Regenerative Medicine Institute (AU), Children's Hospital at Westmead (AU), ARC Centre of Excellence in Plant Energy Biology (AU), ARC Centre of Excellence in Synthetic Biology (AU), Monash University (AU), Macquarie University (AU)
Victor Chang Cardiac Research Institute, Australian Government, Monash University, Queensland Government, Woodside, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 9%
Cardiomyopathy and Myosin Studies
2.78
DOIOpen Access PDFOpenAlex
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