ABSTRACT The transport and Golgi organization 2 ( TANGO2 ) gene has been identified to cause a rare recessive genetic disorder known as TANGO2‐deficiency disorder (TDD). TDD is a multi‐systemic disorder that can affect different organs including the brain, heart, and muscles, presenting as recurrent metabolic crises, muscle weakness, and neurological symptoms including developmental delay and seizures. In a TANGO2‐KO Cal51 cell line model, we previously showed a significant change in the protein N‐glycomics profile, that was corroborated by RNAseq transcriptomics data that showed increased levels of the respective glycosyltransferases. To investigate the in vivo effects of TANGO2‐KO on the glycans in the brain of a mouse model, we profiled the polysialic acid (polySia), glycosaminoglycans (GAGs), glycolipid glycans (GSLs), and protein N‐ and O‐glycans (NGs, OGs) of the cortex of the TANGO2‐KO mice using the Same Sample Sequential Multi‐Glycomics workflow. Overall, we observed a significant decrease in chondroitin sulfate GAG disaccharides, and also a decrease in sialylation across the GSLs, NGs, and OGs, resulting in an overall large decrease in negatively charged glycoconjugates. When compared with a parallel data‐dependent label‐free proteomics of the tissue from the same mouse model, the glyco‐enzymes, sialic acid synthase (NANS), and chondroitin polymerizing factor (CHPF) were found to be significantly downregulated in the brain, correlating with the changes observed by the multi‐glycomics analysis. This overall decrease in negatively charged glycoconjugates due to the loss of TANGO2 function may thus relate to the neurological impairments of TDD.
Moh et al. (Thu,) studied this question.