Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy.
Humans
Interferon-Induced Helicase, IFIH1
/ genetics
Heterozygote
Interferon Type I
/ metabolism
Mutation
Male
Mitochondria
/ metabolism
Female
Immunity, Innate
/ genetics
Exonucleases
/ metabolism
HEK293 Cells
Exoribonucleases
/ genetics
Cytosol
/ metabolism
RNA, Double-Stranded
/ metabolism
Immunoglobulin E
/ blood
Genes, Dominant
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
03
06
2023
accepted:
22
07
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39107301
doi: 10.1038/s41467-024-50878-w
pii: 10.1038/s41467-024-50878-w
doi:
Substances chimiques
Interferon-Induced Helicase, IFIH1
EC 3.6.4.13
IFIH1 protein, human
EC 3.6.1.-
Interferon Type I
0
Exonucleases
EC 3.1.-
Exoribonucleases
EC 3.1.-
RNA, Double-Stranded
0
Immunoglobulin E
37341-29-0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
6685Subventions
Organisme : National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)
ID : 32250410295
Organisme : National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)
ID : 82125015
Informations de copyright
© 2024. The Author(s).
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