Researchers find a genetic cause of lupus

Researchers find a genetic cause of lupus

27th April 2022 

A team of international researchers have identified a genetic cause of lupus. Researchers of the study pinpointed that DNA mutations in a gene that senses viral RNA represents one cause of the chronic condition, affecting approximately 1 in 1,000 people living in the UK. It is important to note that this genetic cause is not the sole trigger for everyone affected by lupus.

Researchers of the study sequenced the whole DNA genome of a juvenile systemic lupus erythematosus (JSLE) patient called Gabriela, who was diagnosed with severe lupus at the age of seven. A severe case such as this, with early onset of symptoms, is a rarity and is commonly associated with a single genetic cause, unlike adult-onset lupus. 

The researchers that carried out the genetic analysis identified a single point mutation in the Toll Like Receptor 7 (TLR7) gene. Furthermore the researchers discovered other cases of severe lupus where this gene was also mutated. 

The team used CRISPR gene-editing which was introduced into mice in order to confirm that the mutation caused the autoimmune disease. The mice went on to develop lupus and displayed lupus-like symptoms, thus providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery. 

Prof Carola Vinuesa, senior author and principal investigator says “It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA in about the last 60 years. This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise”.

Co-director of CACPI, Professor Nan Shen, adds “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments”.

The study indicates that the mutation causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine, making it more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as ‘foreign’ or ‘damaged’ and attack it. 

Results from the study may also provide further explanation about why lupus is around ten times more frequent in females than in males. Females have two copies of the X chromosomes where TLR7 lies, in comparison to males who only have one X chromosome. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. Therefore, females with a mutation in this gene can have two functioning copies of TLR7. 

Co-author of the study, Dr Carmen de Lucas Collantes, states that “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery”. Whilst this specific cause of lupus offers hope as the target for developing new treatments, it should be noted that this will take a long time before becoming available to lupus patients.

Professor Anisur Rahman, University City London (UCL);
“This work from the group of Professor Carola Vinuesa, has added identifying Toll Like Receptor 7 (TLR7) as a potential therapeutic target in lupus. We know that the immune system is not working properly in patients with lupus but identifying the exact immune abnormality that is causing problems in individual patients is very important. There are rare types of lupus, usually diagnosed mainly in children, where the disease is caused by a problem in a single gene. The team started with a patient who had monogenic lupus of this type and identified that the problem was a mutation in the TLR7 gene. This particular mutation increases the activity of TLR7 (a gain of function mutation). They then used genetic modification to introduce exactly the same mutation into mice – and the mice developed lupus. They did further tests on those mice to find out which particular cells of the immune system were behaving abnormally. This research can be put together with other evidence showing that increased TLR7 signalling may play an important role in causing lupus in both humans and mice. Therefore, in the future, treatments that target TLR signalling may become useful in patients with lupus”.


Paul Howard, Chief Executive (LUPUS UK);
“This is very exciting for the community of people living with lupus because it represents a hopeful target for the development of new treatments. We need a wider range of effective medications to treat the disease which also have fewer side-effects than currently available treatments. It is also wonderful to see so much interest in this discovery, which will help raise the profile of lupus research and how vital it is.”


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