Ellen Phiddian
Cosmos science journalist
A group of international researchers have identified a genetic mutation that’s responsible for causing lupus.
It’s the first time that a mutation on a specific gene has been linked to the autoimmune disease. While not all patients carry this mutation, the researchers believe that their discovery will help to find better treatments.
A paper describing the discovery is published in Nature.
Senior author Dr Vicki Athanasopoulos, a researcher at the Australian National University’s John Curtin School of Medical Research, says that researchers have known that there’s a genetic component for a while – but it’s recent advances in genetic technology that have allowed them to make this breakthrough.
“We know that the environment plays a big role, and hormones, and things like that. But from studies using identical twins, monozygotic twins, we know that there is a genetic component,” says Athanasopoulos.
“There’s been these databases, which contain genes that we think are associated with lupus. But this is the first time we’ve actually been able to prove that a particular gene, when it’s mutated, will cause lupus.
“A lot of that is because of advances in technology where we can now generate mutations in the genomes of animals, for example – or cell lines – using what’s called CRISPR-Cas9 technology.”
The problematic gene itself codes for a protein called Toll-like receptor 7, or TLR7. It operates in the immune system, where it helps to sense RNA that comes from viruses.
The researchers examined a mutation in the TLR7 gene that was present in a seven-year-old girl with severe lupus.
When they used CRISPR to cause this mutation in mice, the mice also developed lupus-like symptoms.
“Mice carrying the mutant TLR7 protein developed a condition that mimicked severe autoimmune disease in human patients, providing evidence that the TLR7 mutation causes lupus,” says lead author Grant Brown, a PhD student at ANU.
This evidence, combined with other experiments on mutated TLR7 proteins, allowed the researchers to conclude that this gene was a culprit.
There’s more than one mutation on the TLR7 gene that might have this effect.
“We did have other lupus patients that had different mutations in the same gene,” says Athanasoloulos.
“We looked at some of those, and they seem to behave in a similar way, in that the mutation makes the protein overactive.”
But they also found lupus patients who don’t have a mutated TLR7 gene.
“That’s what we’re trying to unravel: what is causing disease in those particular patients?” says Athanasopoulos.
The TLR7 gene may also play a role in similar chronic conditions.
“We strongly believe that TLR7 and the pathway that it acts in might actually be important in other autoimmune diseases,” says Athanasopoulos.
“We are looking to see how important this gene is in other autoimmune diseases. But we suspect that it’s going to play a role.”
And the genetic mutation potentially explains why lupus is nine times more common in women than in men: the TLR7 gene sits on the X chromosome.
“This means females with an overactive TLR7 gene can have two functioning copies, potentially doubling the harm,” explains senior author Professor Carola Vinuesa, a researcher at ANU and the UK’s Francis Crick Institute.
The researchers are hoping that their CRISPR-based mouse model can be used to test potential lupus treatments which target the TLR7 mutation.
“This newly generated mouse model provides us with a framework to continue to understand the immune system and how autoimmune diseases develop in humans,” says Brown.
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