Scientists discover a genetic cause of lupus in the genome of a Spanish girl

A team of researchers with Spanish participation has identified mutations in the DNA of a gene that detects viral RNA as the cause of lupus, a chronic disease that causes inflammation of organs and joints, affects movement, the skin and causes fatigue.

Gabriela is today a teenager, but when she was only seven years old she was diagnosed with severe lupus. An analysis of its genome has made it possible to identify a genetic mutation as the cause of this autoimmune disease, which opens the way for the development of new treatments, 'Nature' publishes this Wednesday.

Equipment researchers with Spanish participation has identified mutations in the DNA of a gene that detects viral RNA as the cause of lupus, a chronic disease which causes inflammation of organs and joints, affects movement, the skin and causes fatigue.

A case like Gabriela's, severe and with an early onset of symptoms, is rare and indicates a single genetic cause, so scientists sequenced the entire DNA genome.

To confirm that the TLR7 mutation causes lupus, the team used CRISPR gene editing to introduce it into mice, who developed the disease and showed similar symptoms.

The protagonist of this story, Gabriela named both the mouse model and the mutation, which she called “kika.” says in a statement at the Francis Crick Institute (United Kingdom), one of the participants in the study.

The lead author of the research, Carola Vinuesa, from the Francis Crick Institute and the Australian National University, noted that this is the first time that a TLR7 mutation has been shown to cause lupus, “providing clear evidence of one of the ways "in which this disease can arise."

The identification of TLR7 "put an end to a diagnostic odyssey and brings with it the hope that there will be more specific therapies for Gabriela and other lupus patients who are likely to benefit from this discovery," according to co-author Carmen Lucas Collantes, from Hospital Infantil Universitario Niño. Jesús and the Autonomous University, both in Madrid.

Gabriela remains in contact with the investigation team and, cited in the statement, hopes "This finding gives hope to people with lupus and makes them feel that they are not alone in the fight against this battle."

The teenager today hoped that "research can continue and end in a specific treatment that can benefit so many lupus warriors who suffer from this disease."

Finding effective treatments for lupus “has been a great challenge” and the immunosuppressants used can have serious side effects and leave patients more susceptible to infections, highlights Vinuesa, who recalls that In the last 60 years, the US Food and Drug Administration (FDA) has only approved one new treatment.

Although it is possible that only a small number of people with lupus have variants in TLR7, confirming a “causal relationship” between that mutation and the disease allows us to begin searching for more effective treatments, highlights Nan Shen of the Shanghai Institute of Rheumatology. .

The mutation identified by the researchers 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 to incorrectly identify healthy tissue as foreign or damaged and create an attack against it, the statement explains.

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 lupus is about ten times more common in women than in men. Because TLR7 is located on the X chromosome, women have two copies of the gene, while men have one.

Normally, in women one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is usually incomplete. This means that women with a mutation in this gene can have two functional copies.

Researchers are now working with pharmaceutical companies to explore the development or repurposing of existing treatments targeting the TLR7 gene. And they hope that treating this gene can also help patients with related diseases.