Systemic lupus erythematosus, or simply lupus, is a chronic autoimmune condition that affects around five million people worldwide. It is thought to be caused by a combination of genetic and environmental factors, but no single gene or group of genes has yet been confirmed to be directly causative of this condition. Now, publishing their findings in Nature, an international group of scientists has identified a novel mutation in the genome of a Spanish girl, Gabriela, who was diagnosed with lupus at the very early age of seven.
'This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise,' said the principal investigator of the study, Professor Carola Vinuesa, at the Centre for Personalised Immunology, Canberra, Australia, and now group leader at the Francis Crick Institute, London.
Whole genome sequencing was carried out on Gabriela's DNA, revealing a single missense mutation in the TLR7 gene, which causes a tyrosine amino acid to be replaced with a histidine. Using CRISPR, a genome-editing approach, this mutation was introduced into the TLR7 gene of mice. The mice went on to develop lupus-like symptoms, confirming the causative nature of the missense mutation.
The TLR7 gene is responsible for encoding an immune receptor protein which recognises viral RNA by binding to guanosine. Through signalling pathways, other immune cells are recruited to mount a response against the infected cells or tissues. The missense mutation identified by the team causes the TLR7 immune receptor protein to become much more sensitive to the presence of guanosine than normal. This causes the protein to become overactive, attacking healthy tissue and causing lupus. This type of mutation is called a gain-of-function mutation.
Lupus affects nine times more women than men, which could be explained by this discovery. The TLR7 gene is carried on the X chromosome, of which females carry two copies, while males carry only one. 'This means females with an overactive TLR7 gene can have two functioning copies, potentially doubling the harm,' Professor Vinuesa explained.
The current treatment options for lupus are immunosuppressants, which leave a patient's immune system weak and vulnerable to infections. The discovery of this novel mutation could pave the way for new avenues of personalised treatments for lupus, potentially reducing the dependency on immunosuppressants. The scientists are now working with pharmaceutical companies to develop new drugs or modify existing ones targeting the TLR7 gene.
Professor Nan Shen, co-director of the China Australia Centre of Personalised Immunology, said: '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.'