Why the study?
The underlying mechanism contributing to disease onset in response to specific triggers in TANGO2-deficient patients with episodic rhabdomyolysis and cardiac arrhythmia remains unclear.
A zebrafish model of Tango2 deficiency demonstrates that loss of Tango2 leads to growth defects, early lethality, and altered glycerolipid metabolism, providing mechanistic insights into TANGO2-related rhabdomyolysis.
Zebrafish Tango2 loss models growth and muscle defects; extends mechanistic insights but leaves open human translation.
Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components, which leads to myoglobinuria and, in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here, we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of skeletal muscle defects in response to extrinsic triggers, similar to TANGO2-deficient patients. Using lipidomics, we identified alterations in the glycerolipid pathway in tango2 mutants, which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.
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Kim et al. (2023) studied this question.
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