Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy

Idiiatullina, E; Al-Azab, M; Lin, M; Hrovat-Schaale, K; LIU, Z; Li, X; Guo, C; Chen, X; Li, Y; Gao, S; Cui, J; Zhou, W; Liu, L; Zhang, Y; Masters, SL

Author(s): Idiiatullina, E; Al-Azab, M; Lin, M; Hrovat-Schaale, K; LIU, Z; Li, X; Guo, C; Chen, X; Li, Y; Gao, S; Cui, J; Zhou, W; Liu, L; Zhang, Y; Masters, SL;
Details: Publication Year 2024-08-06,Volume 15,Issue #1,Page 6685
Journal Title: Nature Communications
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 IFNalpha, 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.
Publisher: Springer Nature
Keywords: Humans; *Interferon-Induced Helicase, IFIH1/genetics/metabolism; *Heterozygote; *Interferon Type I/metabolism/genetics; Mutation; Male; Mitochondria/metabolism/genetics; Female; Immunity, Innate/genetics; Exonucleases/metabolism/genetics; HEK293 Cells; Exoribonucleases/genetics/metabolism; Cytosol/metabolism; RNA, Double-Stranded/metabolism/genetics; Immunoglobulin E/blood/immunology; Genes, Dominant
Research Division(s): Inflammation
PubMed ID: 39107301
Publisher's Version: https://doi.org/10.1038/s41467-024-50878-w
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-50878-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-024-50878-w.pdf - (3.09MB, application/pdf)

Creation Date: 2024-08-14 09:49:35

Last Modified: 2024-08-14 10:00:22