Does the gene variant HAQ-STING shield against the COPA syndrome?

Last Updated on March 14, 2025 by Joseph Gut – thasso

March 10, 2025 – Does a gene variant shield against the COPA syndrome, a devastating inherited disease? The COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis. Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia patterns clubbing of fingernails too.

For more than 15 years, Dr. Shum, MD, a pulmonologist at UC San Francisco, has tried to understand the random path of devastation that a rare genetic condition, i.e. the COPA syndrome, carves through the families it affects. While many of those who carry the according mutation develop severe lung hemorrhaging as children, others never get the disease at all. Overall, the COPA syndrome is rare, perhaps affecting a few thousand individuals in the U.S., many of whom are not diagnosed. The discovery of the COPA mutation sparked efforts worldwide to raise awareness of the disease, understand it and work toward a cure.

Dr. Shum and a team of collaborators have now found a variation in a separate gene that prevents the COPA syndrome. Most interestingly, the team found that some relatives of COPA syndrome patients remained healthy, despite having the disease-causing mutation to the COPA gene, because they also had a protective variant of another gene known as HAQ-STING. When the scientists engineered the protective variant into diseased COPA lung cells, the cells got better.

Thinking along the way of clinical treatmant of individuals affected with COPA syndrome, this discovery could usher in a new gene therapy for a condition that for now can only be managed with frequent intensive care and immunosuppressant drugs. So, the researchers really think HAQ-STING could be a gene therapy tool and a clear step toward a cure of the COPA syndrome said Dr. Shum, the senior author of the paper dealing with the dominantly protection bv HAQ STING alleles from clinical penetrance of the COPA syndrome, which appeared in the Journal of Experimental Medicine.

The detection of the role of HOA-STING stems from clinical observations in that, when COPA was mutated, as is the case in people with COPA syndrome, STING went awry. Every individual needs STING to fight off occasional infections and get rid of viruses, but in patients with COPA syndrome, STING is on all the time. This causes a lot of inflammation, and for reasons that aren’t totally clear, it damages the lungs, kidneys and joints, explained Dr. Shum. But the researchers knew that STING had a variant, called HAQ-STING, that appeares in over a third of the population. They wondered if it might be able to neutralize the effects of the COPA mutation and explain its inconsistent effects on families. To test their hypothesis, they needed the cooperation of dozens of patients, and their healthy family members as well.

One of these is the family of a girl in an emergency room who had severe bleeding in the lungs. It wasn’t clear what was causing her condition. Dr; Shum suspected a genetic cause when the girl’s mother revealed that the girl’s sister had nearly identical symptoms. Since early childhood, both sisters had routinely visited UCSF emergency rooms to be treated for their unusual combination of life-threatening bleeding in the lungs and rheumatoid arthritis. The clinicians investigated how far these symptoms extended through the girl’s family tree, including some far distant family members and some patients outside their family from around the world.

Overall, the researchers assembled health records and DNA samples from 26 patients with COPA syndrome from around the world. They also put nine healthy patient  relatives with the COPA mutation through several rounds of testing, including CT scans and blood tests for inflammation, to make sure they did not have any symptoms of the disease. Then, the team sequenced the STING gene in every patient and relative. They found that all the healthy relatives had HAQ-STING, while none of the COPA syndrome patients had it.This is the first report of a common allele providing total protection from a severe rare genetic disorder. The researchers then extended their investigations into an in vitro approach by taking lung cells from a patient with COPA syndrome and treating them with HAQ-STING, akin to gene therapy in a petri dish. Even though these cells already had other forms of STING, the addition of HAQ-STING brought their immune signals back into balance. Taken together these finding are indicative that HAQ-STING could be part of a gene-therapeutic treatment of patients suffering from COPA syndrome. A rather exciting clinical perspective

See here a sequence on the HAQ-STING discovery:

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