The genome contains the sequences for protein-coding genes, but before those seuquences are translated into protein, they have to be transcribed into RNA molecules, which are processed by the cell. RNA molecules can be modified in many ways during that processing, and both post-transcriptional and post-translational modifications enable cells to use one gene transcript to create many different proteins. One type of modification that is common in mammals is the conversion of A (adenosine) bases in pre-mRNA to I (inosine). The ADAR (adenosine deaminase acting on RNA) enzyme catalyzes A-to-I RNA editing, which occurs in many genes. A-to-I RNA editing is also thought to play a role in some human diseases, such as ALS, epilepsy, depression, schizophrenia, and inflammatory disorders. It's also been linked to hypermutation of the measles virus.
New research reported in Nature has shown that genetic variants that cause a reduction of A-to-I RNA editing are linked to an increase in the risk of disorders that are related to immunity or autoimmunity, such as inflammatory bowel disease, psoriasis, and type 1 diabetes. The researchers suggested that a protein, which normally acts as a sensor for viruses, mistakenly identifies certain RNA molecules that don't carry the right A-to-I edits as foreign, causing an autoimmune reaction.
Previous research has connected impaired ADAR function to autoimmune disorders. In this study, the scientists analyzed genetic variants that impact RNA editing. Using post-mortem human tissue from 838 donors in the Genotype-Tissue Expression (GTEx) catalog, the investigators used computational tools to identify gene variants that influence the binding of ADAR and RNA molecules. The researchers looked for variants that were prevalent in genomic regions that have been linked to an increase in disease risk.
This effort revealed that genetic variants associated with a reduction in RNA editing were often found among genetic variants that have been linked to diseases related to the immune system, including coronary artery disease, lupus, and multiple sclerosis, The variants impacting RNA editing were also reducing editing, not increasing it. This seems to indicate that impaired ADAR editing can lead to health problems.
Some people carry mutations in the ADAR1 gene. If another, specific mutation is also found in this gene, the carrier may seem to be vigorously battling a viral infection in early life. This disorder is called Aicardi-Goutieres Syndrome. A different report also published in Nature investigated the impact of these mutations.
With a mouse model of these mutations, researchers found that the mutated ADAR1 can lead to the activation of ZBP1, another protein that causes cell death. But other evidence showed that if ADAR1 is not functioning normally in people, ZBP1 seems to cause the immune system to attack the body's own tissues.
ADAR seems to influence autoimmune disease in several ways.
Sources: Genotype-Tissue Expression (GTEx) Program; Qin Li et al, Nature 2022; Hubbard et al, Nature 2022
