We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB–dependent IL-1β responses differently in different cell types.

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We thank the children and their families for participating, and F. Iserin, V. Colomb, F. Rüemmele and V. Valayannopoulos for taking care of them. We particularly thank L. Abel, A. Durandy, P. Génin, B. Neven, M. Veron, J.W. Verbsky and R. Weil. H. Walczak (Imperial College London), K. Iwai (Osaka University) and A. Smahi (INSERM U781 Necker hospital, Paris Cité Sorbonne University) provided antibodies and cells. This work was partly funded by US National Center for Advancing Translational Sciences and National Center for Research Resources, US National Institutes of Health (NIH; 8UL1TR000043), St. Giles Foundation, Jeffrey Modell Foundation, Rockefeller University, INSERM, Paris Descartes University, US National Institute of Allergy and Infectious Diseases (R21AI085523; J.-L.C. and D.C.), NIH (5P01AI061093; J.-L.C.), NIH (R01AR050770; V.P.), Canceropole Ile de France (2007; A.I.), European Community Network of Excellence-Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation (LSHC-CT-2005-018683; E.L. and A.I.), Thrasher Research Fund (C. Prando), Institut de Recherches Servier (E.L., F.A. and A.I.) and Manton Foundation (L.D.N.).

Author information

Author notes

    • Bertrand Boisson
    • , Emmanuel Laplantine
    • , Carolina Prando
    • , Alain Israël
    • , Jean-Laurent Casanova
    •  & Capucine Picard

    These authors contributed equally to this work.


  1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, USA.

    • Bertrand Boisson
    • , Carolina Prando
    • , Avinash Abhyankar
    • , Giraldina Trevejo-Nunez
    • , Dusan Bogunovic
    •  & Jean-Laurent Casanova
  2. Laboratory of Molecular Signaling and Cell Activation, Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Associée (URA) 2582, Institut Pasteur, Paris, France.

    • Emmanuel Laplantine
    •  & Alain Israël
  3. Laboratory of Genetic Disorders of Childhood and Pediatric Clinic, A. Nocivelli Institute for Molecular Medicine, Department of Pathology, Spedali Civili and Pediatric Clinic, University of Brescia, Brescia, Italy.

    • Silvia Giliani
    • , Evelina Mazzolari
    •  & Donatella Vairo
  4. Department of Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.

    • Elisabeth Israelsson
    •  & Damien Chaussabel
  5. Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.

    • Zhaohui Xu
    • , Alma-Martina Cepika
    • , Virginia Pascual
    •  & Damien Chaussabel
  6. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U980, Necker Medical School, Paris, France.

    • Laura Israël
    • , Maya Chrabieh
    • , Marjorie Hubeau
    • , Anne Puel
    • , Jean-Laurent Casanova
    •  & Capucine Picard
  7. Paris Descartes Université, Sorbonne Paris Cité, France.

    • Laura Israël
    • , Maya Chrabieh
    • , Marjorie Hubeau
    • , Damien Bonnet
    • , Pierre Quartier
    • , Jean-Christophe Fournet
    • , Anne Puel
    • , Jean-Laurent Casanova
    •  & Capucine Picard
  8. Washington University School of Medicine and Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease Research, Saint Louis, Missouri, USA.

    • Donna MacDuff
    •  & Herbert W Virgin
  9. Reference Center for Complex Congenital Heart Defects, Assistance Publique Hôpitaux de Paris (AP-HP), Necker Enfants Malades Hospital, Paris, France.

    • Fanny Bajolle
    •  & Damien Bonnet
  10. Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker Enfants Malades Hospital, Paris, France.

    • Marianne Debré
    • , Pierre Quartier
    • , Jean-Laurent Casanova
    •  & Capucine Picard
  11. Institut Pasteur, Structural and Cellular Biochemistry Unit, CNRS, URA 2185, Paris, France.

    • Fabrice Agou
  12. Experimental Laboratory Immunology, Department of Microbiology and Immunology, Biomedical Science Group, Catholic University of Leuven, Leuven, Belgium.

    • Xavier Bossuyt
  13. Pathology Laboratory, AP-HP, Raymond Poincarré, Garches, France.

    • Caroline Rambaud
  14. Department of Pathology, Spedali Civili and University of Brescia, Brescia, Italy.

    • Fabio Facchetti
  15. Pathology Laboratory, AP-HP, Necker Enfants Malades Hospital, Paris, France.

    • Jean-Christophe Fournet
  16. Division of Immunology and The Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Luigi D Notarangelo
  17. Study Center for Primary Immunodeficiencies, AP-HP, Necker Enfants Malades Hospital, Paris, France.

    • Capucine Picard


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B.B., E.L., S.G., A.A., L.I., G.T.-N. and M.C. performed experiments. C. Prando, A.A. and D.V. performed genetic analysis. F.B., M.D., E.M., D. Bonnet., P.Q., L.D.N. and C. Picard provided all the clinical data for the patients. D. Bogunovic., D.M., M.H., F.A. and H.W.V. provided reagents and suggestions. X.B. and C. Picard performed immunological explorations. C.R., F.F. and J.-C.F. performed histological analysis. E.I., Z.X., A.-M.C., V.P. and D.C. performed transcriptome analysis. A.I., J.-L.C. and C. Picard coordinated the study, and B.B., E.L., C. Prando, V.P., D.C., L.D.N., A.P., A.I., J.-L.C. and C. Picard wrote the manuscript. All authors discussed the results and commented on the manuscript. B.B., E.L. and C. Prando equally contributed as first authors. S.G., E.I., Z.X. and A.A. equally contributed as second authors. V.P., D.C., L.D.N. and A.P. equally contributed as second to last authors. A.I., J.-L.C. and C. Picard equally contributed as last authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jean-Laurent Casanova.

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