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Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy

Elina Idiiatullina1,2,3, Mahmoud Al-Azab1,4, Meng Lin1

  • 1Department of Genetics and Endocrinology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.

Nature Communications
|August 6, 2024
PubMed

Insights

A rare REXO2 gene mutation causes interferonopathy by allowing mitochondrial RNA to activate the MDA5 immune sensor. This leads to a type I interferon signature and an inborn error of immunity.

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Mitochondrial RNA (mtRNA) in the cytosol can activate the MDA5 innate immune sensor, leading to type I interferon production and autoinflammatory diseases.
  • Dysregulation of mitochondrial homeostasis is implicated in various autoinflammatory conditions.

Purpose of the Study:

  • To investigate the role of a dominant-negative mutation in the mitochondrial exonuclease REXO2 in causing interferonopathy.
  • To elucidate the molecular mechanism by which REXO2 mutations trigger the MDA5 pathway.

Main Methods:

  • Clinical phenotyping of a patient with a heterozygous de novo REXO2 mutation (p.T132A).
  • Analysis of skin biopsy, circulating IgE, inflammatory cytokines (including IFNα), and peripheral blood mononuclear cell (PBMC) transcriptional profiles.
  • Biochemical assessment of REXO2 (T132A) enzymatic activity and its effect on wild-type REXO2 function.

Main Results:

  • The patient presented with a characteristic skin rash, elevated IgE, and consistently high levels of inflammatory cytokines, including IFNα.
  • Transcriptional analysis of PBMCs revealed a type I interferon gene signature.
  • The REXO2 (T132A) mutation impaired RNA cleavage activity, inhibited wild-type REXO2, and led to cytosolic accumulation of mitochondrial dsRNA, activating the MDA5 pathway.

Conclusions:

  • A dominant-negative mutation in REXO2 can cause interferonopathy by disrupting mitochondrial RNA processing and triggering MDA5-mediated type I interferon production.
  • Aberrant accumulation of cellular nucleic acids due to impaired REXO2 function results in continuous innate sensor activation, leading to an inborn error of immunity.
  • This study highlights REXO2 as a critical regulator in preventing autoinflammation driven by endogenous RNA.

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