New study on TANGO2 illuminates the path of a rare disease

There are only 110 patients diagnosed with TANGO2 Deficiency Disorder (TDD) worldwide – although there could be up to 9,000 unidentified.

Children with this disease are not able to obtain energy from the lipids present in their cells. Therefore, once carbohydrate reserves are depleted – for example, after a high fever, a viral infection or hours of fasting – they suffer potentially fatal metabolic crises.

Vivek Malhotra‘s laboratory, at the Centre for Genomic Regulation (CRG), discovered two decades ago the TANGO (Transport ANd Golgi Organization proteins) gene family, a family of 14 genes involved in the secretion and transport of proteins in the cell.

In their latest study, published today in the Journal of Cell Biology, the authors have investigated what TANGO2 does at the molecular level and why its alteration causes life-threatening symptoms. They have shown that TANGO2 is located in the mitochondria (the “energy factories” of cells). It also binds directly to a molecule called acyl-CoA, which is used to “activate” lipids that are processed for energy production in the mitochondria.

“People with TDD have a reduced capacity to do this, so their cells are not able to generate the types of fat that are needed to obtain energy,” says Agustín Luján, postdoctoral researcher at the CRG and first author of the study, in which Ombretta Foresti and other members of the Vivek laboratory have collaborated, as well as researchers in Japan, London and the United States.

The findings were also possible thanks to the collaboration with the patient association of the TANGO2 Research Foundation, which provided biological samples from patients with this disease.

“We are grateful to the scientific teams around the world working to put this puzzle together and have a positive impact on patients and families living with TDD.”

Kasha Morris, co-founder of the TANGO2 Research Foundation

We spoke with Agustín Luján about TANGO proteins, this recent study and what it means to study a rare disease.

———–

In 2016, mutations in TANGO2 were discovered to cause a rare disease now recognized as TANGO2 Deficiency Disorder (TDD). How is the cause of such a rare disease discovered?

Several doctors – Seema Lalani, from Baylor College of Medicine, USA, and Laura Kremer, from the University of Munich, Germany – found a group of patients who shared clinical peculiarities, such as neuromuscular alteration with rhabdomyolysis, metabolic crises and muscle weakness. Although they shared symptoms with other known neuromuscular and neurometabolic diseases, they did not completely fit with these other diseases. That is why they decided to do a complete genome sequencing of these patients, and found that they all had a mutation in both alleles of the TANGO2 gene.

How important is the collaboration of doctors, researchers and families in the study of rare diseases?

I believe that medical-scientific collaboration is important for all diseases in general. But particularly, in the case of rare diseases, the lack of knowledge leads to basic science playing a fundamental role in the race to provide clues about the mechanisms involved in each case and thus find treatments to manage the disease and improve the quality and life expectancy of the patient as quickly as possible.

TANGO2 deficiency is a clear example of the importance of families in this process. They formed a community of affected families and created a Foundation (TANGO2 Research Foundation) that worked tirelessly to raise awareness of the disease in the medical field and encourage basic research. They also provided critical information about the clinical characteristics they observed in their sons and daughters so that doctors and researchers could understand what molecular mechanisms could be involved in the absence of TANGO2.

In addition, every two years, they organize a congress where patients, families, doctors and scientific personnel meet. This allows us to know what the needs of patients and their families are and thus effectively focus medical and scientific efforts for the benefit of the affected community.

In our case, we are in contact with both the TANGO2 Research Foundation, which brings together world medical experts in this field, and with the multidisciplinary medical group at the Sant Joan de Déu Hospital that follows the 11 DTT patients in Spain.

How did you start studying this, why did you become interested in this protein?

I studied Medicine at the National University of Cuyo (Argentina), then I did a doctorate with a CONICET scholarship on STIs and galectins, and later I came to Vivek’s laboratory to do a postdoc. When I arrived, Vivek told me about the TANGO proteins and his interest in continuing to discover the function of each of these proteins that his laboratory had described in 2006. Since most of its history was TANGO1, I Googled TANGO2, and when I saw that there was a foundation involved, with patients, a rare disease and a lot to contribute, it was a mix that immediately fascinated me.

Studying the biology of rare diseases – in addition to being essential for people who suffer from them and their families – can help us understand human health in general.

How is it justified to study a disease that only 100 people in the world have?

As a doctor, one of the most difficult things is to tell a patient’s parents that we do not know what their son or daughter has, or even if they have a diagnosis, that there is no cure or they have a low life expectancy or quality of life. In the case of rare diseases, low prevalence, lack of data or lack of resources mean that they are undertreated. That is why basic research is so important in these cases, offering hope to those who do not have it today.

But also, studying a rare disease is not just solving a problem for a few, because understanding the functioning of an unknown protein or a mechanism that has been little studied at the cellular level allows us to understand basic concepts of human biology that may be related to other diseases and conditions. For example, understanding the functioning of TANGO2 indirectly involves mechanisms that affect neuromuscular, neuroendocrine and cardiac diseases.

“This study could help us understand heart or muscle diseases in the general population. Millions of people struggle with heart problems or abnormal fat metabolism, and the underlying chemistry isn’t all that different”
Vivek Malhotra (CRG)

Regarding this last article, how can it help to achieve better treatment or diagnosis of the disease?

This study allows us to understand the location and main interaction of TANGO2. Understanding this is essential to be able to search within the mechanistic pathway in which TANGO2 participates, which components above and below TANGO2 could supply its function. In this way, we could stimulate the overactivation of these components to compensate for the absence of TANGO2.