TANGO2 binds crystallin alpha B and its loss causes desminopathy

Maike Stentenbach, Laetitia A. Hughes, Samuel V. Fagan, Blake Payne, Danielle L. Rudler, Stefan J. Siira, Tim McCubbin, Anaëlle Chopin, Kara L. Perks, Judith A. Ermer, James Hendry, Teagan S. Er, Shanti Balasubramaniam, Joel A. Eliades, Livia C. Hool, Nicolle H. Packer, Edward S. X. Moh, Benjamin S. Padman, Oliver Rackham () and Aleksandra Filipovska ()
Additional contact information
Maike Stentenbach: Perth Children′s Hospital
Laetitia A. Hughes: Perth Children′s Hospital
Samuel V. Fagan: Perth Children′s Hospital
Blake Payne: Perth Children′s Hospital
Danielle L. Rudler: Perth Children′s Hospital
Stefan J. Siira: Perth Children′s Hospital
Tim McCubbin: The University of Queensland
Anaëlle Chopin: Perth Children′s Hospital
Kara L. Perks: Perth Children′s Hospital
Judith A. Ermer: University of Western Australia
James Hendry: Perth Children′s Hospital
Teagan S. Er: The University of Western Australia
Shanti Balasubramaniam: The Children’s Hospital at Westmead
Joel A. Eliades: Monash University
Livia C. Hool: The University of Western Australia
Nicolle H. Packer: Macquarie University
Edward S. X. Moh: Macquarie University
Benjamin S. Padman: Perth Children′s Hospital
Oliver Rackham: Perth Children′s Hospital
Aleksandra Filipovska: Perth Children′s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60563-1

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