Major genetic discovery identifies the cause of lupus
[Nov. 20, 2022: Alice Deeley, The Francis Crick Institute]
Age spots of redness on the face from systemic lupus erythematosus. (CREDIT: Velimir Zeland / Shutterstock)
An international team of researchers has identified DNA mutations in a gene that senses viral RNA, as a cause of the autoimmune disease lupus, with the finding paving the way for the development of new treatments.
Lupus is a chronic autoimmune disease which causes inflammation in organs and joints, affects movement and the skin, and causes fatigue. In severe cases, symptoms can be debilitating and complications can be fatal.
There is no cure for the disease, which affects around 50,000 people in the UK, and current treatments are predominantly immune-suppressors which work by dialing down the immune system to alleviate symptoms.
In their study, published in Nature today, the scientists carried out whole genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.
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In their genetic analysis, carried out at the Centre for Personalised Immunology at the Australian National University, the researchers found a single point mutation in the TLR7 gene. Via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, they identified other cases of severe lupus where this gene was also mutated.
To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice. These mice went on to develop the disease and showed similar symptoms, 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.
Carola Vinuesa, senior author and principal investigator at the Centre for Personalised Immunology in Australia, co-director of CACPI, and now group leader at the Crick 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”.
Professor Nan Shen, co-director of CACPI 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 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 to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it.
TLR7 structure 6IF5. Regions in red were restrained through all simulations with a harmonic restraint of force constant 5 kcal/mol/Å2. Guanosine and R848 illustrated with binding geometries from crystal structures 5GMF and 5GMH14. L1-L3 indicate ligand atoms used for Boresch restraints, which were restrained relative to the three depicted protein alpha carbons of residues F408, G379 and F325 (not to scale). Distances and angles in gold, and dihedrals in pink show the values for the 6DoF Boresch restraints. Additional geometric relationships between the restrained atoms, as measured from the starting structure, are shown in grey smaller print. Boresch dihedral restraints are relative to the two atoms connecting either side of the location of print. White hydrogen spheres and red oxygen spheres show the atoms used in the calculation for determining the number of waters within 3.5 Å of the tail region that each ligand interacted with. (CREDIT: Nature)
Interestingly, other studies have shown mutations that cause TLR7 to become 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 10 times more frequent in females than in males. As TLR7 sits on the X chromosome, females have two copies of the gene while males have one. 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. This means females with a mutation in this gene can have two functioning copies.
Peddy diagrams used to establish relatedness. Each red dot represents a child/parent pair (child mother and child father). The grey dot is a no-relatedness control. Coefficient of relatedness should be 0.5 for a parent-child pair. ibs0: the number of sites at which the 2 samples shared no alleles (should approach 0 for parent-child pairs). ibs2: the number of sites in which the child vs parent samples where both hom-ref, both het, or both hom-alt. Shared_hets: the number of sites at which both child and parent samples were hets. (b) Ancestry check using Peddy (proband and parents are purple dots). (CREDIT: Nature)
Dr Carmen de Lucas Collantes, a co-author of this study says: “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”.
Gabriela, who remains in touch with the research team and is now a teenager, says: “I hope this finding will give hope to people with lupus and make them feel they are not alone in fighting this battle. Hopefully the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”
The researchers are now working with pharmaceutical companies to explore the development of, or the repurposing of existing treatments, which target the TLR7 gene. And they hope that targeting this gene could also help patients with related conditions.
Carola adds: “There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus. TLR7 may also play a role in these conditions.”
Carola has started a new laboratory at the Francis Crick Institute to further understand the disease-causing mechanisms that occur downstream of key mutations like the one found on the TLR7 gene.
Symptoms of Lupus:
No two cases of lupus are exactly alike. Signs and symptoms may come on suddenly or develop slowly, may be mild or severe, and may be temporary or permanent.
Lupus facial rash. A typical sign of lupus is a red, butterfly-shaped rash over your cheeks and nose, often following exposure to sunlight. (CREDIT: Creative Commons)
Most people with lupus have mild disease characterized by episodes — called flares — when signs and symptoms get worse for a while, then improve or even disappear completely for a time.
The signs and symptoms of lupus that you experience will depend on which body systems are affected by the disease. The most common signs and symptoms include:
Joint pain, stiffness and swelling
Butterfly-shaped rash on the face that covers the cheeks and bridge of the nose or rashes elsewhere on the body
Skin lesions that appear or worsen with sun exposure
Fingers and toes that turn white or blue when exposed to cold or during stressful periods
Shortness of breath
Headaches, confusion and memory loss
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Note: Materials provided above by The Francis Crick Institute. Content may be edited for style and length.
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