Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy

Elina Idiiatullina, Mahmoud Al-Azab, Meng Lin, Katja Hrovat-Schaale, Ziyang Liu, Xiaotian Li, Caiqin Guo, Xixi Chen, Yaoying Li, Song Gao, Jun Cui, Wenhao Zhou, Li Liu (), Yuxia Zhang () and Seth L. Masters ()
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Elina Idiiatullina: Guangzhou Medical University
Mahmoud Al-Azab: Guangzhou Medical University
Meng Lin: Guangzhou Medical University
Katja Hrovat-Schaale: Bashkir State Medical University
Ziyang Liu: Guangzhou Medical University
Xiaotian Li: Guangzhou Medical University
Caiqin Guo: Guangzhou Medical University
Xixi Chen: Guangzhou Medical University
Yaoying Li: Sun Yat-sen University Cancer Center
Song Gao: Sun Yat-sen University Cancer Center
Jun Cui: Sun Yat-sen University
Wenhao Zhou: Guangzhou Medical University
Li Liu: Guangzhou Medical University
Yuxia Zhang: Guangzhou Medical University
Seth L. Masters: Guangzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Mitochondrial RNA (mtRNA) in the cytosol can trigger the innate immune sensor MDA5, and autoinflammatory disease due to type I IFN. Here, we show that a dominant negative mutation in the gene encoding the mitochondrial exonuclease REXO2 may cause interferonopathy by triggering the MDA5 pathway. A patient characterized by this heterozygous de novo mutation (p.T132A) presented with persistent skin rash featuring hyperkeratosis, parakeratosis and acanthosis, with infiltration of lymphocytes and eosinophils around small blood vessels. In addition, circulating IgE levels and inflammatory cytokines, including IFNα, are found consistently elevated. Transcriptional analysis highlights 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. These results demonstrate that in the absence of appropriate regulation by REXO2, aberrant cellular nucleic acids may accumulate and continuously trigger innate sensors, resulting in an inborn error of immunity.

Date: 2024
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DOI: 10.1038/s41467-024-50878-w

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