| HRA004834
(Controlled Access)
|
Mitochondrial RNA (mtRNA) in the cytosol can trigger the innate immune sensor MDA5, and autoinflammatory disease due type I IFN. Here we describe a new disease in this class of interferonopathy, due to a dominant negative mutation of the mitochondrial exonuclease REXO2. This heterozygous de novo mutation (p.T132A) caused persistent skin rash featuring hyperkeratosis, parakeratosis and acanthosis with infiltration of lymphocytes and eosinophils around small blood vessels. There was also consistent elevation in circulating IgE levels, inflammatory cytokines including IFNa, and a type I IFN gene signature in PBMC. Mechanistically, REXO2 (T132A) lacks the ability to cleave RNA, and inhibits the activity of wild-type REXO2. This leads to an accumulation of mitochondrial dsRNA in the cytosol, which is recognized by MDA5, leading to the associated type I IFN gene signature. Therefore, appropriate regulation of mitochondrial RNA by REXO2 is required to prevent this novel inborn error of immunity. |
