Research

Lina Ghaloul-Gonzalez, MD (Co-PI)
Jerry Vockley, MD, PhD (Co-PI)

TANGO2-related disorder is a genetic disorder caused by changes that inactivate both copies of the TANGO2 gene. While these changes have been identified in affected children, how they cause the characteristic symptoms of this disorder is unknown. Importantly, even patients who have the exact same mutation can have symptoms that vary from mild to severe for reasons that are unknown. TANGO2 is speculated to transport newly produced proteins in the cell to their final functional location. However, studies of this process have been limited. In preliminary experiments, I have shown that the ability of TANGO2 deficient cells (cells lacking TANGO2 protein from patients) to generate energy from mitochondria (the energy producing part of the cell) is impaired. I speculate that this defect arises from impaired transport of proteins necessary for normal mitochondrial function. It is important that once proteins are made, they are directed to the correct location in cells. My experiments will examine the normal location of TANGO2 protein in cells, and how that location is affected by mutations in TANGO2. Further studies will characterize energy production caused by TANGO2 mutations. In sum, these experiments will help us better understand the consequences of TANGO2 deficiency on the body and develop novel treatments for the disease.

Single-Institution Award: $25,000

Edor Kabashi, PhD

Rhabdomyolysis (RM) is an acute injury of skeletal muscle that results from environmental or congenital causes. TANGO2 is a recently discovered gene, whose mutations have been identified as a major cause of RM associated with encephalopathy. At the cellular level, TANGO2 protein presumably regulates the organization of the Golgi apparatus and the endoplasmic reticulum (ER), as well as mitochondrial function. In two different, but related monogenic disease leading to RM flares, our team has found that muscle cells exhibiting abnormal ER functions lead to an excessive inflammatory cascade. This can be caused partially due to defective lipid membranes. Given our findings in those two diseases, and state of the art in TANGO2 disease, we propose that perturbed vesicular ER/Golgi transport and/or mitochondrial functions from TANGO2 mutations contribute to the symptoms.

In order to follow our hypothesis, and to be able to find a potential treatment, we need good cellular and animal models that complement each other to study the disease. Zebrafish has emerged as an excellent model to study neurological, cardiac, and metabolic diseases that appear in humans. Our team has large experience on the study of the pathophysiology of neurological diseases such as ALS in zebrafish. Furthermore, zebrafish larvae serve as a great platform to screen medicines in a multi-well format, such that several medicines can be analyzed at the same time. Thus, we envision to create a mutant TANGO2 zebrafish using genetic engineering techniques (transient morpholino-mediated knockdown and stable CRISPR/Cas9 lines), in order to have a full organism model where we can, at the same time, do molecular investigations and screen medicines.

Taken together, combining molecular studies in primary human muscular cells and evaluating physiological parameters in TANGO2 mutant zebrafish, we expect to set the basis for the translation of potential drugs to higher vertebrates to protect patients from inevitably RM and neurological regression during febrile illness.

Multi-Institution Award: $50,000

Claudia Soler-Alfonso, M.D., F.A.C.M.G.

TANGO2-related metabolic encephalopathy and arrhythmias is a severe medical condition presenting with muscle weakness, delayed developmental milestones, abnormal heart rhythms, and seizures. Patients can also present with life-threatening emergencies known as “metabolic crisis”. Individuals experiencing a metabolic crisis show low blood sugars, increased lactic acid, and increased ammonia levels in their blood. We do not understand the triggers and mechanisms behind the metabolic crisis. At our metabolic center, we observed strong similarities in patients with a TANGO2 metabolic crisis and metabolic crisis in patients unable to process fats in their diets due to specific genetic defects known as fatty acid oxidation disorders. However, standard biochemical tests in patients with TANGO2 do not show the same kinds of typical abnormalities seen in patients with fatty acid oxidation disorders. We do know, however, that TANGO2 patients have fewer episodes of metabolic decompensation when they are treated similarly to people with fatty acid oxidation disorders. Our research goal is to study TANGO2 patients using a technique called untargeted metabolomics to identify metabolic patterns in the blood that could give us an idea of why they experience episodes. This technique identifies hundreds of compounds instead of only a few dozen. It is a much more comprehensive way to look at chemicals in the blood. Our previous preliminary observations suggest that patients with TANGO2 have low levels of pantothenic acid (or vitamin B5), which is involved in fatty acid processing. Our research goal is to identify a specific metabolic profile in TANGO2 patients, with particular attention to vitamin levels and fat acid oxidation markers. If a definite pattern of deficiency is proven, we may be able to give patients extra amounts of a given vitamin, or other nutrients to make their symptoms better and prevent episodes altogether.

Single Institution Award: $25,000