DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling

J Clin Immunol. 2022 Aug;42(6):1310-1320. doi: 10.1007/s10875-022-01287-5. Epub 2022 Jun 7.


Background: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans.

Objectives: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human.

Methods: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022.

Results: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients.

Conclusions: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).

Keywords: ANCA; Apoptosis; DNASE1L3; Interferon-stimulated genes; Nucleic acids; Systemic lupus erythematosus; Type I interferon.

Publication types

  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Antineutrophil Cytoplasmic / genetics
  • Chromatin
  • DNA
  • Endodeoxyribonucleases* / genetics
  • Endodeoxyribonucleases* / metabolism
  • Humans
  • Inflammatory Bowel Diseases*
  • Interferon Type I* / genetics
  • Interferons
  • Lupus Erythematosus, Systemic* / genetics
  • Lupus Nephritis* / diagnosis
  • Lupus Nephritis* / genetics
  • Phenotype
  • Vasculitis* / diagnosis


  • Antibodies, Antineutrophil Cytoplasmic
  • Chromatin
  • Interferon Type I
  • DNA
  • Interferons
  • DNASE1L3 protein, human
  • Endodeoxyribonucleases