2. Academic Validation
  3. Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy

Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy

  • Nat Commun. 2024 Aug 6;15(1):6685. doi: 10.1038/s41467-024-50878-w.
Elina Idiiatullina # 1 2 3,  Mahmoud Al-Azab # 1 4,  Meng Lin 1,  Katja Hrovat-Schaale 2 4,  Ziyang Liu 1,  Xiaotian Li 1,  Caiqin Guo 1,  Xixi Chen 1,  Yaoying Li 5,  Song Gao 5,  Jun Cui 6,  Wenhao Zhou 1,  Li Liu 7,  Yuxia Zhang 8,  Seth L Masters 9 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Genetics and Endocrinology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Therapy and Nursing, Bashkir State Medical University, Ufa, Russia.
  • 3 Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, USA.
  • 4 Department of Medical Microbiology, Faculty of Medicine, University of Science and Technology, Aden, Yemen.
  • 5 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 7 Department of Genetics and Endocrinology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China. liliuchina@qq.com.
  • 8 Department of Genetics and Endocrinology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China. yuxia.zhang@gwcmc.org.
  • 9 Department of Genetics and Endocrinology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China. seth.masters@hudson.org.au.
  • 10 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. seth.masters@hudson.org.au.
  • 11 Department of Medical Biology, The University of Melbourne, Parkville, Australia. seth.masters@hudson.org.au.
  • 12 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia. seth.masters@hudson.org.au.
  • 13 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. seth.masters@hudson.org.au.
  • # Contributed equally.
PMID: 39107301 DOI: 10.1038/s41467-024-50878-w
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.

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