Discovery of new TNIP1 gene mutation offers new hope for disease that can lead to blindness

An international team of scientists, including researchers from the Australian National University (ANU), has identified a rare, mutated version of a protein called TNIP1 that causes a chronic autoimmune disease similar to Sjögren’s syndrome, a condition that causes extreme dryness of the eyes and mouth that can lead to blindness if left untreated.

The TNIP1 mutation may also be responsible for more serious autoimmune diseases, researchers say, including lupus, a debilitating disease that causes inflammation of organs and joints, skin rashes and fatigue. In extreme cases, the disease can be fatal.

Scientists say they have successfully reversed the mutation’s harmful effects in mice, bringing them one step closer to developing new drug therapies that have the same effect in humans.

These findings could lead to new treatments tailored to Sjögren’s syndrome and lupus caused by TNIP1 gene variants. The article is published in the journal Natural immunology.

Lead author Dr Arti Medhavy, who carried out the work as part of his PhD at ANU, said it was the first time scientists had shown that a variation in the TNIP1 protein was responsible for autoimmune disease in humans.

“Proteins are essential for our growth, development and general health, but they have a limited lifespan. Once they have served their purpose, they are deactivated,” said Dr Medhavy, who now works at Griffith University’s Institute of Biomedicine and Glycomics.

“That’s where TNIP1 comes in. It works in unison with the cell’s waste management system. TNIP1 essentially acts as a gatekeeper for the immune system, removing obsolete proteins and transporting them to the cell’s degradation sites where they are broken down, recycled and reused.

“Genetic material is normally packaged in specific compartments of the cell, including the cell’s energy factories called mitochondria. The same genetic material, however, can set off alarms in the immune system if it is detected outside these specialized compartments.

“Importantly, TNIP1’s role in the waste management system includes the removal of damaged or leaky mitochondria, which helps maintain healthy cells.

“But the mutated version of the TNIP1 protein is less efficient at processing these protein and mitochondrial waste products, leading to a buildup of toxic substances in cells. If these waste products are not processed, these substances can become harmful to the cell and trigger the immune system, ultimately promoting the onset of autoimmune diseases.”

It is estimated that one in ten Australians suffer from some form of autoimmune disease. Study co-author and ANU Fellow Dr Vicki Athanasopoulos said Sjögren’s syndrome is an unpleasant and debilitating condition that affects more than 270,000 Australians.

She said there was a need to develop tailored treatments that specifically target the proteins and biochemical pathways that lead to the onset of autoimmune diseases, rather than suppressing the entire immune system.

“There is currently no cure for autoimmune diseases. Current therapies help patients better manage their disease, but these treatments have unpleasant side effects that make patients more susceptible to infections, which can reduce their quality of life,” said Dr. Athanasopoulos.

The researchers identified the TNIP1 mutation in two unrelated patients, one from Australia and one from China. Although both had the same TNIP1 mutation, one of the patients had signs and symptoms of lupus, while the other appeared to have symptoms of Sjögren’s syndrome.

Using gene editing technology, the researchers introduced the human-equivalent TNIP1 mutation into mice. They found that mice carrying the mutation developed a disease that mimicked the symptoms of Sjögren’s disease seen in one of the human patients.

“The mutant TNIP1 protein is similar to the TLR7 mutation that causes lupus in that it affects the same biochemical pathway. Work is already underway in pharmaceutical companies to develop new drugs and modify existing ones to inhibit the TLR7 pathway,” said Dr. Athanasopoulos.

According to Dr. Medhavy, although the two patients with the TNIP1 mutation had slightly different forms of autoimmune disease, they both had abnormally high levels of IgG4 antibodies in their blood.

“The abnormally high presence of IgG4 in both patients is interesting because clinicians may be able to use IgG4 as a biomarker for TNIP1-mediated autoimmune disease,” she said.

“By screening patients with autoimmune disease for elevated levels of IgG4, clinicians may be able to test whether patients also have the TNIP1 mutation, which would indicate that they might respond well to therapies targeting the same TLR7 pathway.”