Genetic Defect Tied to Autoimmune Diseases

Rare mutations lead to several different disorders.

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By Tina Heman Saey, Science News

Rare variations in a single gene can lead to a wide variety of autoimmune disorders, including diabetes, lupus and rheumatoid arthritis, a new study shows.

The gene in question encodes an enzyme called sialic acid acetylesterase or SIAE, which regulates the activity of the immune system’s antibody-producing B cells. About 2 percent to 3 percent of people with autoimmune disorders have defects in the enzyme that allow B cells to run amok and make antibodies that attack the body, a team led by Shiv Pillai of Massachusetts General Hospital in Charlestown and Harvard Medical School reports online June 16 in Nature.

“It’s a seminal paper because it is so applicable to a wide variety of autoimmune diseases, says Judy Cho, a Yale geneticist not associated with the study. The finding suggests that enhancing the enzyme’s activity could help treat disease in people with autoimmune disorders. 

Previously, Pillai’s group showed that mice lacking SIAE develop a lupuslike disease in which high levels of antibodies attack the body’s own proteins. The researchers decided to examine the enzyme in people who, like the mice, make high levels of autoimmune antibodies. “One hundred percent, I was confident that we would find nothing,” Pillai says.

Instead, in a small study of 19 people, including 13 with autoimmune disorders and a comparison group of six healthy people, the researchers found that a person with Crohn disease and one with rheumatoid arthritis had genetic mutations inactivating the enzyme. The team expanded the study and eventually identified variants of the enzyme in 27 of 923 people with autoimmune disease and in 17 of 648 healthy people.

Tests showed that most SIAE variants found in people with autoimmune disorders disrupt the enzyme’s normal function, while all but two of the healthy people were found to carry variants that don’t interfere with the enzyme’s activity. The study estimated, albeit with a wide range of uncertainty, that people with defects in the enzyme have nine times greater odds of developing autoimmune disease than those with functioning versions of SIAE.

The researchers found that one variant, designated M89V, doesn’t affect the enzyme’s function but does block its secretion. Some healthy people in the study carried one copy of this secretion-defective enzyme, with a normal copy to compensate. But eight people with autoimmune disorders, including rheumatoid arthritis, lupus, multiple sclerosis and type 1 diabetes, had two copies of the defective enzyme.  

“These functional studies very nicely complement the genetics,” Cho says. Because the researchers could pinpoint specific biochemical defects, the study has a leg up on some genome-wide searches for common genetic variants that contribute to disease. Such studies usually can’t identify the biological effects of the variants they uncover, Cho says.

Since two healthy people do have disruptions in SIAE activity, the researchers can’t say for sure that defects in the enzyme cause the autoimmune disorders in patients. But “it’s about as close as you’re going to get to proof in humans,” Pillai says. Those two healthy people may still get autoimmune disorders later in life, he says, or defects in SIAE may be just the last straw for people with many different genetic variations predisposing them to autoimmune disease.

Whether changes in the enzyme are all that is necessary to trigger autoimmune disease “or if there are more things, we don’t know,” Pillai says. “I suspect more things. I suspect it’s not enough.”

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