Research

PROJECT

Children with TANGO2 disease have multi system diseases, however, the heart disease is the major cause of death. The heart appears healthy at baseline, yet during crises electrical abnormality (arrhythmia) occurs and it is often resistant to standard therapy, which can cause lethality. Thus, understanding the mechanistic nature of these episodes, can help us design treatment strategies to minimize the chance of them happening and terminating these crises when they do occur.

With the support from the TANGO2 foundation, we have generated a single iPSC-CM (induced pluripotent stem cell differentiated cardiomyocytes) cell line from a patient with the common exon 3-9 deletion. These beating heart cells recapitulated the electrical abnormalities of TANGO2 patients in crises and importantly, we found the electrical abnormalities can be fully corrected by re-expressing normal TANGO2 in these cells. We believe this is the first cardiac model that faithfully recapitulate the condition of the TANGO2 patients and holds great potential to decipher disease mechanism and test promising treatment.

In the current proposal, we will generate isogenic (TANGO2 mutation corrected) controls of 3 additional patient iPSC lines carrying different mutations in TANGO2 gene. Then we will differentiate these iPSC (patient cells and their matching controls) into CM and investigate channel activities and trafficking as well as possible metabolic triggers for arrhythmia.

At the completion of the current proposal, we hope to confirm the molecular etiology of arrhythmia is due to trafficking defect of channels and identify potential metabolic stressors that induces arrhythmia as well as potential treatment strategies.

Award: $148,000

PROJECT

All human cells have a number of different compartments that include the nucleus, the endoplasmic reticulum and mitochondria to name a few. Each of these compartments has a unique set of proteins that give the compartment specific functions. Yet, compartments receive material from other areas of the cell in a process referred to as membrane traffic. Our research programs have focused on the consequences of mutations in human genes that affect mitochondrial function and membrane traffic. A prerequisite to devising a treatment plan for individuals with specific gene mutations is knowing what the affected protein does in a cell. In our current TANGO2 research project we focus on the cell physiological consequences of human TANGO2 deficiency. Our experimental approaches include live-cell-imaging, biochemical assays, metabolite profiling, proteomic analysis, and a large-scale chemical screening platform for drug discovery. One of our main interests is the elucidation of the cellular location of TANGO2 and the factors that influence this location. Moreover, we aim to gain more insights into the influence of TANGO2 on cellular energy metabolism as well as on membrane trafficking pathways, particularly between the endoplasmic reticulum and the Golgi. In this context we also hope to identify interaction partners of the TANGO2 protein, which would be of great help in understanding the biological function of TANGO2. Finally, we will apply a drug screening platform to search for chemical compounds that influence TANGO2 function and are able to mitigate the effects of TANGO2 deficiency.​

Multi-Institution Award: $50,000

Christina Miyake, MD MS (Co-PI – TCH)
Lilei Zhang, PhD (Co-PI – BCM)
Diana Milewicz, MD PhD (Collaborator – UT Health Sciences)
Heinrich Taegtmeyer, MD PhD (Collaborator -UT Health Sciences)

TANGO2 families have helped contribute to the natural history study and based on this data we have determined that metabolic crisis are triggered predominantly by illness, decreased oral intake, and heat. While the symptoms of TANGO2 disease are similar to mitochondrial and fatty acid oxidation disorders, the mechanism and role of TANGO2 remains unknown. We believe that understanding the mechanism behind TANGO2 may be best studied by looking at the heart because the heart is affected in all children during crisis and because it demonstrates the most severe effects. We believe that TANGO2 may play an important role in maintaining energy for cardiac cells. Stressors such as fasting or heat affect protein function in the heart. Ion channels are critical for the heart to beat normally and they maintain electrolyte balance in the heart cells. When alterations occur, this can lead to QTc prolongation, a hallmark of TANGO2 crisis, and heart failure, another new finding we are beginning to see.

Our study has 3 aims. First we will create induced pluripotent stem cell (iPSC) line that will be used for this study but can be used in future studies looking at all different organ systems. Second we will use the iPSC cells to create human heart cells. And lastly we will take these heart cells and put these cells under different stressors that are known to trigger crisis in TANGO2 children (example: we will “fast” the cells, denying the cells sugar and we will place the cells under heat). We will then study the effects that these stressors produce. We will specifically look to see how these stressors affect the cells metabolism, the ECG and heart function using specialized equipment in the Zhang lab. Then we will try and “rescue” the cells by adding certain nutrients and vitamins to see if we can reverse the effects.

The first aim of this study which uses fibroblasts from a TANGO2 child to create induced pluripotent stem cells will not only provide the foundation for us to study heart cells in this study but this will also provide the ability for other researchers in the future to study the different organs affected by TANGO2. This iPSC cell is a specialized cell that is the precursor cell for all cells within the body. By using an actual TANGO2 child’s cells, we will essentially be recreating the cells from that child’s body with all of their specific genetic information. These cells therefore, when studied, will provide insights into that specific child but the information can be generalized to other children with the same genetic change.

Single Institution Award: $25,000