TANGO2 deficiency disease is predominantly caused by a lipid imbalance

Abstract

TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

Keywords: Lipid imbalance; Metabolic crises; Neurodevelopmental disease; TANGO2 deficiency disease.

Fig. 1.

Features and phenotypic variation of TANGO2 deficiency disease. A collection of neurodevelopmental, muscular and systemic defects, including developmental delay, life-threatening metabolic crises and cardiac arrhythmias typically appear in late infancy in TANGO2 deficiency disease (Berat et al., 2021; Dines et al., 2019; Hoebeke et al., 2021; Mingirulli et al., 2020; Miyake et al., 2022; Schymick et al., 2022). The severity varies with the mutation type and its mono- or bi-allelic status, and it also varies within individuals of the same family (Miyake et al., 2022; Schymick et al., 2022), suggesting the contribution of other factors. Percentages indicating the prevalence among patients with TDD are shown.

Fig. 2.

TANGO2 homologs. Multiple sequence alignment of TANGO2-like proteins from the worm Caenorhabditis elegans (HRG-9 and HRG-10), the bacterium Shewanella oneidensis, the fruit fly Drosophila melanogaster, mice (Mus musculus), humans (Homo sapiens) and zebrafish (Danio rerio). GenBank sequences were downloaded in FASTA format, aligned with Clustal Omega (Madeira et al., 2022), and manually edited and annotated. Note that Clustal Omega orders sequences according to similarity scores. For easier comparison, the human sequence has been extracted and reported below with further annotations. The adjacent taxonomy tree illustrates sequence relatedness (arbitrary units used to compare branching architectures within a guided tree). Residue color coding and symbols indicating residue conservation are indicated. In the human sequence, tyrosine (Y) 116, implicated in heme binding in worms and bacteria, is highlighted (rounded square). This tyrosine is conserved in all the orthologs shown except for C. elegans HRG-10. Residues in human TANGO2 affected by pathological mutations are circled; the likely pathologic deletion of residues 190-197 is boxed. Variants of pathological significance were extracted from UniProt (UniProt, 2023). UniProt sequence identifiers: C. elegans HRG-9 (Q22009) and HRG-10 (Q9U1Q8), S. oneidensis (Q8EKG7), D. melanogaster (Q9VYA8), M. musculus (P54797), H. sapiens (Q6ICL3) and D. rerio (Q6AXK1).

Fig. 3.

Pathways of coenzyme A synthesis. Pantothenate (vitamin B5), the obligate precursor of coenzyme A (CoA), is generally ingested either by food or vitamin supplements. A five-step process converts this vitamin into CoA. In order to regulate CoA levels, a balance between de novo synthesis and salvage versus degradation and synthesis inhibition must be achieved. Defects in salvage could lead to altered lipid metabolism and/or oxidative stress. CoA salvage is largely mediated by the levels of the antioxidant cysteamine, but a defect in CoA salvage in the absence of TANGO2 could help explain patient phenotypes and why vitamin B5 supplementation alleviates metabolic crises. Red arrows indicate processes involved in CoA salvage, with much of this process involving transport of metabolites into or out of the mitochondria. PANK, pantothenate kinase; PPCS, phosphopantothenoylcysteine synthetase; PPCDC, phosphopantothenoylcysteine decarboxylase; PPAT, phosphopantetheine adenyl transferase; DPCK, dephospho-CoA kinase.