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

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Abstract

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).

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Data Availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

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Acknowledgements

We thank the patients and their parents for participating in this study. This work is dedicated to Pr Rolando Cimaz who passed away last January 29th 2022.

Funding

Y.J.C. received a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01), and the MSDAvenir fund (DEVO-DECODE Project). A.B. was supported by the National Research Agency (France) (ANR-21-CE17-0064–01).

Author information

Authors and Affiliations

  1. The International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France

    Maud Tusseau, Rémi Pescarmona, Anne-Laure Mathieu, Thierry Walzer, Sebastien Viel, Magali Perret & Alexandre Belot

  2. Genetics Department, Lyon University Hospital, Lyon, France

    Maud Tusseau, Gaétan Lesca & Audrey Labalme

  3. University Children’s Hospital University Medical Center Ljubljana, Ljubljana, Slovenia

    Ema Lovšin, Marusa Debeljak & Tadej Avčin

  4. Nephrologie Pediatrique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France

    Charlotte Samaille & Angelique Dachy

  5. Immunology Laboratory, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Benite, France

    Rémi Pescarmona, David Goncalves, Nicole Fabien, Sebastien Viel & Magali Perret

  6. University Department PROMISE ”G. D’Alessandro”, University of Palermo, Palermo, Italy

    Maria-Cristina Maggio

  7. Children’s Hospital, University Clinical Center , Sarajevo, Bosnia and Herzegovina

    Velma Selmanović

  8. Pediatric Nephrology Department, Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia

    Gregor Novljan

  9. Cardiogenetics Laboratory, Biochemistry and Molecular Biology Department, Lyon University Hospital, Lyon, France

    Alexandre Janin

  10. NeuroMyoGene Institute, Lyon 1 University, CNRS UMR 5510, INSERM U1217, Lyon, France

    Alexandre Janin & Louis Januel

  11. University Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, 59000, Lille, France

    Jean-Baptiste Gibier

  12. Centre de Biotechnologie Cellulaire Et Biothèque, Hospices Civils de Lyon, Bron, France

    Emilie Chopin & Isabelle Rouvet

  13. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    Gillian I Rice

  14. Nephrology Unit, Anna Meyer Children Hospital and University of Florence, University of Florence, Florence, Italy

    Paola Romagnani

  15. Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France

    Yanick J. Crow

  16. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK

    Yanick J. Crow

  17. ASST G. Pini, Milan, Italy

    Rolando Cimaz

  18. Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy

    Rolando Cimaz

  19. National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France

    Alexandre Belot

  20. Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 Bd Pinel, 68677, Bron Cedex, France

    Alexandre Belot

Authors
  1. Maud Tusseau
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  2. Ema Lovšin
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  3. Charlotte Samaille
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  4. Rémi Pescarmona
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  5. Anne-Laure Mathieu
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  6. Maria-Cristina Maggio
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  7. Velma Selmanović
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  8. Marusa Debeljak
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  9. Angelique Dachy
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  10. Gregor Novljan
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  11. Alexandre Janin
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  12. Louis Januel
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  13. Jean-Baptiste Gibier
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  14. Emilie Chopin
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  15. Isabelle Rouvet
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  16. David Goncalves
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  17. Nicole Fabien
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  18. Gillian I Rice
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  19. Gaétan Lesca
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  20. Audrey Labalme
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  21. Paola Romagnani
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  22. Thierry Walzer
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  23. Sebastien Viel
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  24. Magali Perret
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  25. Yanick J. Crow
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  26. Tadej Avčin
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  27. Rolando Cimaz
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  28. Alexandre Belot
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Contributions

MT and AB made substantial contributions to the conception or design of the work. MT and AB drafted the manuscript. EL, CS, RP, ALM, MCM, VS, MD, AD, GN, AJ, LJ, JBG, EC, IR, DG, NF, GIR, GL, AL, PR, TW, SV, MP, YJC, TA, and AB were involved in the acquisition, analysis, or interpretation of data. All authors provided critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Alexandre Belot.

Ethics declarations

Ethics Approval

The study was approved by the Leeds (East) Research Ethics Committee (reference number 10/H1307/132) and the Medical Ethics Committee of Sud Est III (Lyon, France).

Consent to Participate

Parental written informed consent was provided for inclusion of clinical data and samples in the study.

Consent for Publication

Written informed consent for publishing the results of this study considering ethical confidentiality and anonymity was obtained from the parents.

Conflict of Interest

The authors declare no competing interests.

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Tusseau, M., Lovšin, E., Samaille, C. et al. DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling. J Clin Immunol 42, 1310–1320 (2022). https://doi.org/10.1007/s10875-022-01287-5

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  • DOI: https://doi.org/10.1007/s10875-022-01287-5

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