TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

Abstract

Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2‐related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism‐induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post‐mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.

The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER‐to‐Golgi transport and at the mitochondria

“…Several studies attempted to show such a function but results have been enigmatic (Table 1). Consistent with one study that showed no redistribution of mannosidase II to the ER in individuals with either a deletion encompassing exons 4-6 or harboring a p.His94Thrfs*3 frameshift variant, 6 we also did not see a change in localization of this Golgi enzyme nor in the Golgi matrix marker p115 in fibroblasts from the three individuals studied here, expanding this result to three other TANGO2 genotypes. It remains to be seen if these findings also hold true for other TANGO2 variants including missense variants.…”

“…On the other hand, a study that examined three TANGO2 isoforms including the canonical one did not find evidence for either Golgi or mitochondrial localization, concluding that the protein was cytosolic. 6 It is noteworthy that the former study did in fact report an Mingirulli et al 7…”

Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect

“…RNA expression of TANGO2 in myoblasts from two patients with the homozygous deletion (P2, P11) and one patient with the homozygous mutation c.262C>T (P18) was reduced by more than 99% and 87% relative to control cells, respectively (Figure 2A). We failed to detect by Western Blotting protein expression of TANGO2 in control and patient myoblasts using the antibody Abcam ref 87576 2,4 at various dilutions and buffers (data not shown). Using the ProteinTech antibody Ref 27846-1-AP, we observed a band at 35Kda in control cells, as expected.…”

“…Neurological impairment can arise before and be aggravated by MC, and varies from normal condition to severe encephalopathy. 4,5 The incidence of TANGO2 disease is unknown, although a large number of patients have recently been described over a short time, with two predominant mutations that suggest a founder effect. 2,5 At the cellular level, TANGO2 protein presumably regulates the organization of the Golgi apparatus and the endoplasmic reticulum (ER), but its exact function is unknown.…”

“…The TANGO2 murine homolog T10 has been shown to localize to mitochondria 6 while palmitate-dependent mitochondrial respiration is significantly reduced in TANGO2 mutant fibroblasts, suggesting a role in energy metabolism. 4,7,8 Moreover, abnormal acylcarnitine species in dried blood spot and urinary excretion of lactate and dicarboxylic acids have been occasionally observed during the acute episodes, whereas mitochondrial studies on muscle biopsies were essentially normal 1,2 or occasionally abnormal with lipid accumulation. 8 Here, we report the clinical and biological findings of a cohort of 20 patients from 14 families with TANGO2 mutations including mitochondrial respiration, palmitate and glutamine fluxes and intracellular characterization in patients' myoblasts.…”