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Mutations in the TANGO2 gene are associated with a severe neurometabolic disorder in humans, often presenting with life-threatening metabolic crisis. However, the function of TANGO2 protein remains unknown. It has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that prior heme-related observations in Caenorhabditis elegans lacking TANGO2 homologs HRG-9 and HRG-10 may be better explained by a previously unreported metabolic phenotype, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as potential factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.

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.

Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases, including myopathies and muscular atrophy. However, the mechanistic understanding of specific components of the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40 , an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive remain poorly understood. To characterize the KLHL40-regulated ubiquitin-modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40a mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy, biosynthetic metabolic processes, and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.

Recent advancements in genetics and technology have led to a greater understanding of the roles of different skeletal muscle proteins in a disease context. Most skeletal muscle proteins’ functions have been uncovered; however, some proteins’ precise roles in the pathophysiology of myopathies remain elusive. Many members of the Kelch family proteins have been investigated for their importance in skeletal muscle maintenance and disease contexts. Mutations in genes encoding KLHL40 result in abnormal muscle function and loss of KLHL30 in vertebrate muscle affects mitochondrial function. In particular, mutations in KLHL40 result in a severe form of nemaline myopathy. This work is focused on investigating skeletal muscle specific-Kelch proteins, KLHL30 and KLHL40, by creating and characterizing cellular disease models in hopes of validating findings from animal models. Future studies will be aimed at creating therapeutics for KLHL30 and KLHL40 deficient neuromuscular diseases.

Mutations in the TANGO2 gene are associated with a severe neurometabolic disorder in humans, often presenting with life-threatening metabolic crisis. However, the function of TANGO2 protein remains unknown. It has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that prior heme-related observations in Caenorhabditis elegans lacking TANGO2 homologs HRG-9 and HRG-10 may be better explained by a previously unreported metabolic phenotype, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as potential factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.

Mutations in the gene cause severe illness in humans, including life-threatening metabolic crises. However, the function of TANGO2 protein remains unknown. Using and other models, it has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that heme-related observations in nematodes may be better explained by a previously unreported metabolic phenotype in these worms, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as key factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.

Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises. However, the function of TANGO2 protein remains unknown. Using Caenorhabditis elegans and other models, it has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that heme-related observations in nematodes may be better explained by a previously unreported metabolic phenotype in these worms, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as key factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.Competing Interest StatementThe following authors have unpaid roles at the TANGO2 Research Foundation: SES, Early Diagnostic and Detection Committee Member VAG, Scientific Advisor Board Member MS, Executive Board Member SJM, Research Committee Member and Scientific Advisory Board ChairFootnotes* This version of the manuscript has been revised to reflect additional literature published since the first version was posted to bioRxiv. The figures have been reformatted, and two additional experiments (nematode survival and swim motility) are now included. Minor additional editorial changes have been incorporated.

Rhabdomyolysis is a clinical emergency characterized by severe muscle damage resulting in the release of intracellular muscle components leading to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are 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 show that loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of muscle defects similar to TANGO2 patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+ release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state of tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and increased our understanding of how specific defects can predispose to environmental triggers in TANGO2-related disorders.

Optimal vancomycin exposure is important to minimize treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We aimed to analyze the impact of initial vancomycin pharmacokinetic/pharmacodynamic (PK/PD) parameters, including the initial vancomycin C trough and the area under the curve (AUC)/minimal inhibitory concentration (MIC) on the outcomes of pediatric MRSA bacteremia. The study population consisted of hospitalized children aged between 2 months and 18 years with MRSA bacteremia, in whom C trough was measured at least one time within the time period of January 2010 to March 2018. Demographic profiles, underlying diseases, and clinical/microbiological outcomes were abstracted retrospectively. During the study period, 73 cases of MRSA bacteremia occurred in children with a median age of 12.4 months. Severe clinical outcomes leading to intensive care unit stay and/or use of mechanical ventilation occurred in 47.5% (35/73); all-cause 30-day mortality was 9.7% (7/72). The median dosage of vancomycin was 40.0 mg/kg/day. There was a weak linear relationship between C trough and the corresponding AUC/MIC ( r = 0.235). ROC curves for achieving an AUC/MIC of 300 suggested that the initial C trough at 10 μg/mL could be used as a cut-off value with a sensitivity of 90.5% and a specificity of 44%. Although persistent bacteremia at 48–72 hours after vancomycin administration was observed more frequently when the initial C trough was < 10 μg/mL and initial AUC/MIC was < 300, initial AUC/MIC < 300 was the only risk factor associated with persistent bacteremia at 48–72 hours (adjusted OR 3.05; 95% CI, 1.07–8.68). Initial C trough and AUC/MIC were not associated with 30-day mortality. Although there was a weak relationship between C trough and AUC/MIC, initial AUC/MIC < 300 could be used as a predictor of persistent MRSA bacteremia at 48–72 hours. Further prospective data on optimal vancomycin dosing are necessary to improve clinical and microbiological outcomes in pediatric MRSA bacteremia.

[This corrects the article DOI: 10.1371/journal.pone.0246191.].[This corrects the article DOI: 10.1371/journal.pone.0246191.].