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This Gene Mutation Breaks the Immune System. Why Has It Survived?

In Greenland in January 2021, a child just under two years old was sick—very sick. And his doctors couldn’t figure out why. He was feverish, vomiting, having seizures. Meningitis was suspected to be the cause; a tuberculosis diagnosis was also being tossed around. The child was transferred to Copenhagen—to Rigshospitalet, the largest hospital in Denmark—for further evaluation.

By March, the child’s doctors were no closer to figuring out why he wasn’t getting better. So they reached out to Trine Mogensen, a professor of immunology at Aarhus University in Denmark. “It was really unclear what this infection was. And there was no evidence of bacterial infection or tuberculosis,” Mogensen says. Stumped, she and her team sequenced the child’s genome to see if this uncovered any clues. “It came out, surprisingly, that there was a genetic mutation,” she says.

What they had found was a mutation in the gene that codes for IFNAR2, a protein that binds to type I interferons. Interferons are a family of proteins that play an essential role in fighting off viral infections. Without type I interferons working well, the child would be unable to mount any kind of immune response to viruses such as Covid-19 and the flu. 

Yet what virus the child was facing was still unclear. So Mogensen got in contact with Christopher Duncan, a clinician-scientist who studies viral immunity and interferons at Newcastle University in the United Kingdom. Duncan had been researching the very same genetic mutation for several years, first documenting it in a 2015 paper in the journal Science Translational Medicine. In that paper, he and his colleagues had found the genetic variant in a family from Ireland. A 13-month-old infant had suffered a severe case of encephalitis—inflammation of the brain—after receiving the MMR vaccine, which contains live (but weakened) forms of the measles, mumps, and rubella viruses. The child’s illness ultimately proved to be fatal. 

Following the publication of that paper, Duncan and his colleagues had been contacted by researchers in Alaska, who had identified a couple of children—unrelated—who had run into major problems with multiple viruses and had the same genetic variant. He was also alerted to two children in northern Canada with a similar condition. 

Knowing this, Mogensen and Duncan went back to the child from Greenland—and finally uncovered the root of his condition. They discovered that three weeks before falling ill, he had also been vaccinated with the live MMR vaccine. (The child survived and is now healthy.) Duncan and Mogensen published their findings in April in the Journal of Experimental Medicine

But now the team wanted to know if there were more people carrying this uncatalogued genetic mutation. They had noted that the boy from Greenland and the children from Alaska were all of Inuit or Alaska Native heritage. They trawled through the genetic records of 5,000 Inuit and found the variant was surprisingly common: In fact, 1 in 1,500 people in the Inuit population were carrying it. “That was hugely surprising,” Duncan says.