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. 

The sheer prevalence of this variant in the Inuit population, and the fact it had gone under the radar for so many years, is the fascinating part of the puzzle. The genetic variant probably arose through the “founder effect,” whereby multiple people end up carrying a mutation that originated in a common ancestor. The effect tends to be seen in populations that descend from relatively small groups of people and that don’t mix much with outsiders. “Because these populations were quite secluded or isolated for centuries, then such a mutation can become more prevalent,” explains Mogensen.

It’s likely that many more children died from carrying this genetic variant before it was discovered. “It’s only recently that we do genetic investigations,” Mogensen explains. And we could see more and more of these genetic mutations emerge from the woodwork as genetic sequencing becomes cheaper and more popular, especially in remote populations. “I think that will uncover a lot of explanations for this huge inter-individual variation we see in how sick people become.” (The findings also emphasize the importance of cataloging the genomes of people other than Europeans.) 

Mogensen now wants to look into more samples from the past to get a clearer picture of just how common this genetic mutation is. If it is prevalent enough, there could be a rationale to add the genetic mutation to newborn screening in countries with Inuit populations. It would mean the children carrying the mutation wouldn’t be given the live MMR vaccine, for instance. The team is now in talks with the chief medical officer in Greenland, Mogensen says.

Much of the existing immunology knowledge has been achieved through work on animal models, a less-than-perfect replica of the intricacies of the human immune machinery. Cases like those documented by Duncan and Mogensen can uncover how immune proteins, like interferons, work and fight infection—and highlight just how indispensable they are. When you can see what happens in humans who lack a part of the immune system, says Duncan, “that’s basically the absolute definitive evidence of what it does.”

The discovery slots into a growing field of immunology that searches for a genetic basis for immune deficiencies—what are known as inborn errors of immunity. Scientists have only just begun to unravel how many immunological mysteries can be explained by a genetic mutation. To date, more than 400 “inborn errors of immunity” have been documented, with no signs of that number slowing down. “Every day, we discover more,” says Ivan Zanoni, an immunologist at Harvard Medical School and Boston Children’s Hospital. 

Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University, has been one of those spearheading the movement. In the same issue of the journal that published Mogensen and Duncan’s findings, Casanova and his colleagues describe a similar genetic variant in seven children with heritage from another remote population: West Polynesians. All of the children were of Samoan descent. “We thought that this could hardly be coincidental,” he says. 

However, this time the mutation was in the gene that codes for IFNAR1, another protein that binds with type I interferons. They decided to test if this genetic variant might be of West Polynesian origin, through the founder effect, and so analyzed populations across the Pacific, from Taiwan to the eastern part of French Polynesia. “To our great surprise, we found that the allele is indeed Polynesian,” Casanova says. “In western Polynesia in particular it’s a common allele,” meaning it can be found in more than 1 percent of the population. 

Not only that, they discovered that the seven children had suffered adverse reactions to the MMR vaccine, as well as to the yellow fever vaccine—another that contains a live virus—and had also fallen severely ill with viral infection. Four of the seven children died. But the main indicator of carrying the variant, the researchers agreed, was an adverse reaction to the MMR vaccine. Following the release of the paper, Australia’s health authorities issued a warning to health care providers, stating that children of West Polynesian heritage who become very unwell in the weeks following the MMR vaccine may need to be assessed for an immune deficiency.

The biggest surprise, Casanova says, is that even without type I interferons, individuals might still be able to deal with lots of viruses. If it was the case that these proteins were essential in fighting off all viral infections, these IFNAR1 or IFNAR2 mutations wouldn't become so common in remote populations, he argues.

Zanoni takes a slightly different stance. He thinks the remoteness of these populations protected them from being exposed to all the viruses that people on the mainland might have encountered, which allowed the variant to be passed down from generation to generation. “The fact that the frequency of the mutation is so high in this population really suggests that it was negatively selected in the general population in the continent,” he says.

Mogensen has a further theory. “We think that since it was becoming so prevalent, there may have been an advantage of having this mutation,” she says. The idea here is that it may have been protective against other infectious diseases, like tuberculosis—but this remains pure speculation, she says. 

Regardless, there are many people around the world walking down the street without this immune protein, says Casanova. “That is just mind-blowing.”

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

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