09 July 2020
Pinpointing the pathogenesis of systemic lupus erythematosus
Published online 30 November 2011
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease afflicting several organs of the body and is known to cause a distinctive butterfly-shaped rash on a person's face. It affects millions worldwide, yet few disease-causing genes are known. A study published in Nature Genetics has now identified a single gene that leads to a rare form of this disease.
A team of researchers from Oman and Saudi Arabia, led by Fowzan Alkuraya from King Faisal Specialist Hospital and Research Center, Riyadh, studied seven Arab families with a history of SLE. They used autozygome and linkage analysis to identify 206 genes linked to the disease.
They identified a single mutation in the gene DNASE1L3, which encodes deoxyribonuclease (DNase),, an enzyme that chops up and breaks down DNA. The mutation inactivates DNase by either causing the mRNA transcript to be degraded or the protein to be misfolded, which was confirmed in human cells.
DNASE1L3 is expressed mostly in macrophages in the liver and spleen, a pattern that makes the inactivating mutation a very likely cause of SLE, suggest the researchers. They propose that the mutated macrophages cannot break down their own or pathogen DNA and the dead cells are packed with DNA. Immune cells then engulf and process the dead cells and produce antibodies against this DNA, causing the individual's own immune system to trigger SLE.
Taken together, these findings are a first step in understanding SLE and developing better therapies, suggest the researchers. They now plan to use the same method to understand other multi-factorial genetic diseases within Arab populations, which are fertile ground for research thanks to a high rate of consanguinity.
- Al-Mayouf, S. M. et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nature Genetics (2011). doi: 10.1038/ng.975