NIH scientists identify gene linked to fatal inflammatory disease in children

Investigators have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Several existing drugs have shown therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which the researchers named STING-associated vasculopathy with onset in infancy (SAVI). The findings appeared online today in the New England Journal of Medicine. The research was done at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health.

"Not only do these discoveries have profound implications for children with SAVI, but they could have a broader impact by helping us to understand other, more common inflammatory conditions," said NIAMS Director Stephen I. Katz, M.D., Ph.D. "Diseases such as lupus share some characteristics with SAVI, so this work may lead to novel insights and possibly new treatments for these debilitating conditions, as well."

The senior author of the study, Raphaela Goldbach-Mansky, M.D., and the co-lead authors, Yin Liu, M.D., Ph.D., Adriana A. Jesus, M.D., Ph.D., and Bernadette Marrero, Ph.D., are in the NIAMS Translational Autoinflammatory Disease Section.

Autoinflammatory diseases are a class of conditions in which the immune system, seemingly unprovoked, becomes activated and triggers inflammation. Normally, the inflammatory response helps quell infections, but the prolonged inflammation that occurs in these diseases can damage the body.

In 2004, Dr. Goldbach-Mansky was called upon to advise on a patient with a baffling problem—a 10-year-old girl with signs of systemic inflammation, especially in the blood vessels, who had not responded to any of the medications her doctors had used to treat her.

She had blistering rashes on her fingers, toes, ears, nose and cheeks, and had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.

By 2010, Dr. Goldbach-Mansky had seen two other patients with the same symptoms. She suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child's parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

The DNA comparison revealed a novel mutation in a gene that encodes a protein called STING, a known signaling molecule whose activation leads to production of interferon, a key immune regulator. When overproduced, however, interferon can trigger inflammation.

"Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling," said Dr. Goldbach-Mansky.