Scientists found a point mutation in the TLR7 gene in a Spanish girl diagnosed with severe lupus at the age of 7, which was later confirmed in other cases.
Image of a patient with Lupus. Photo: Shutterstock.
A group of researchers revealed that they managed to identify mutations in the DNA of a gene that detects viral RNA as the cause of lupusa fact that paves the way for the development of new treatments, as published in Nature.
Carola Vinuesa, main author, assures that “it has been a great challenge to find effective treatments for lupus and the immunosuppressants currently in use can have serious side effects and leave patients more susceptible to infection. The FDA has only approved one new treatment in the last 60 years.”
“This is the first time that a TLR7 mutation has been shown to cause lupuswhich provides clear evidence of one of the ways this disease can arise,” he adds.
The scientists carried out the sequencing of the complete genome of a Spanish girl, named Gabriela, who was diagnosed with lupus serious when I was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.
In the analysis, conducted at the Australian National University Center for Personalized Immunology, the researchers found a single point mutation in the TLR7 gene. Through references from the United States, China and Australia, they identified other cases of lupus severe in which this gene was also mutated.
To confirm that the mutation causes lupus, the team used the gene editing tool CRISPR to introduce it into mice. These animals developed the disease and showed similar symptoms, proving that the mutation in the TLR7 gene was the cause. Both the mouse model and the mutation were baptized as “kika”, by Gabriela, the young protagonist of this discovery.
For his part, researcher Nan Shen adds that “although it is possible that only a small number of people with lupus have variants in TLR7 itself, we know that many patients show signs of overactivity in the TLR7 pathway. By confirming a causal relationship between the gene mutation and the disease, we can start looking for more effective treatments.”
The mutation the researchers identified causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely that it will incorrectly identify healthy tissue as foreign or damaged and mount an attack against it.
Interestingly, other studies have shown that mutations that make TLR7 less active are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system.
The work may also help explain why the lupus It is about 10 times more common in women than in men. Since TLR7 is located on the X chromosome, females have two copies of the gene, while males have only one.
Normally, in females one of the X chromosomes is inactive, but in this section of the chromosome the silencing of the second copy is usually incomplete. This means that women with a mutation in this gene can have two working copies.
Carmen de Lucas Collantes, co-author of the study, explains that “the identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and provides hope that Gabriela and other patients with lupus can benefit from this discovery.
Gabriela is still in contact with the investigation team and is now a teenager. “I hope this finding gives hope to people with lupus and make them feel that they are not alone in fighting this battle,” she says. Hopefully the research can continue and end up in a specific treatment that can benefit so many warriors of the lupus who suffer from this disease.
The researchers are now working with pharmaceutical companies to explore the development or repurposing of existing treatments targeting the TLR7 gene. And they hope that targeting this gene could also help patients with related diseases.
Carola adds that “there are other systemic autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, which fit into the same general family as lupus. TLR7 may also play a role in these diseases.”
Now he has launched a new laboratory at the Francis Crick Institute to further understand disease-causing mechanisms that occur downstream of key mutations such as the one found in the TLR7 gene.
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