[en] 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 24(th) 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).
Disciplines :
Immunology & infectious disease Pediatrics
Author, co-author :
Tusseau, Maud; The International Center of Research in Infectiology, Lyon University, INSERM ; Genetics Department, Lyon University Hospital, Lyon, France.
Lovšin, Ema; University Children's Hospital University Medical Center Ljubljana, Ljubljana,
Samaille, Charlotte; Nephrologie Pediatrique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
Pescarmona, Rémi; The International Center of Research in Infectiology, Lyon University, INSERM ; Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite,
Mathieu, Anne-Laure; The International Center of Research in Infectiology, Lyon University, INSERM
Maggio, Maria-Cristina; University Department PROMISE "G. D'Alessandro", University of Palermo, Palermo,
Selmanović, Velma; Children's Hospital, University Clinical Center , Sarajevo, Bosnia and
Debeljak, Marusa; University Children's Hospital University Medical Center Ljubljana, Ljubljana,
Dachy, Angélique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Nephrologie Pediatrique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
Novljan, Gregor; Pediatric Nephrology Department, Children's Hospital, University Medical Centre
Janin, Alexandre; Cardiogenetics Laboratory, Biochemistry and Molecular Biology Department, Lyon ; NeuroMyoGene Institute, Lyon 1 University, CNRS UMR 5510, INSERM U1217, Lyon,
Januel, Louis; NeuroMyoGene Institute, Lyon 1 University, CNRS UMR 5510, INSERM U1217, Lyon,
Gibier, Jean-Baptiste; University Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and
Chopin, Emilie; Centre de Biotechnologie Cellulaire Et Biothèque, Hospices Civils de Lyon, Bron,
Rouvet, Isabelle; Centre de Biotechnologie Cellulaire Et Biothèque, Hospices Civils de Lyon, Bron,
Goncalves, David; Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite,
Fabien, Nicole; Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite,
Rice, Gillian I; Division of Evolution and Genomic Sciences, School of Biological Sciences,
Lesca, Gaétan; Genetics Department, Lyon University Hospital, Lyon, France.
Labalme, Audrey; Genetics Department, Lyon University Hospital, Lyon, France.
Romagnani, Paola; Nephrology Unit, Anna Meyer Children Hospital and University of Florence,
Walzer, Thierry; The International Center of Research in Infectiology, Lyon University, INSERM
Viel, Sebastien; The International Center of Research in Infectiology, Lyon University, INSERM ; Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite,
Perret, Magali; The International Center of Research in Infectiology, Lyon University, INSERM ; Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite,
Crow, Yanick J; Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of
Avčin, Tadej; University Children's Hospital University Medical Center Ljubljana, Ljubljana,
Cimaz, Rolando; ASST G. Pini, Milan, Italy. ; Department of Clinical Sciences and Community Health, University of Milano,
Belot, Alexandre; The International Center of Research in Infectiology, Lyon University, INSERM ; National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, ; Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère
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