Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Two kindreds with autosomal recessive HOIL1 deficiency.
Figure 2: HOIL-1 complete deficiency.
Figure 3: HOIL-1 is required for full TNF- and IL-1β–induced activation of NF-κB in fibroblasts.
Figure 4: Impaired recruitment of NEMO to cytokine receptors in the patients' fibroblasts.
Figure 5: Transcriptome analysis of TNF or IL-1β stimulation of primary fibroblasts.
Figure 6: Whole-blood analysis reveals a new hyperinflammatory disorder in HOIL-1–deficient patients.
Figure 7: HOIL-1-deficient monocytes display hyperproduction of IL-6 upon IL-1β stimulation.

Accession codes

Primary accessions

Gene Expression Omnibus


  1. 1

    Masters, S.L., Simon, A., Aksentijevich, I. & Kastner, D.L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    McDermott, M.F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    CAS  PubMed  Google Scholar 

  4. 4

    Ombrello, M.J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Puel, A., Picard, C., Ku, C.L., Smahi, A. & Casanova, J.L. Inherited disorders of NF-κB-mediated immunity in man. Curr. Opin. Immunol. 16, 34–41 (2004).

    CAS  PubMed  Google Scholar 

  6. 6

    Doffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat. Genet. 27, 277–285 (2001).

    CAS  PubMed  Google Scholar 

  7. 7

    Courtois, G. et al. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Invest. 112, 1108–1115 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Casanova, J.L., Abel, L. & Quintana-Murci, L. Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu. Rev. Immunol. 29, 447–491 (2011).

    CAS  PubMed  Google Scholar 

  9. 9

    von Bernuth, H. et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).

    CAS  PubMed  Google Scholar 

  11. 11

    Picard, C. et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89, 403–425 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Casanova, J.L. & Abel, L. Inborn errors of immunity to infection: the rule rather than the exception. J. Exp. Med. 202, 197–201 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Casanova, J.L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).

    CAS  PubMed  Google Scholar 

  14. 14

    Picard, C., Casanova, J.L. & Puel, A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin. Microbiol. Rev. 24, 490–497 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    von Bernuth, H. et al. Septicemia without sepsis: inherited disorders of nuclear factor-κB-mediated inflammation. Clin. Infect. Dis. 41 (suppl. 7), S436–S439 (2005).

    CAS  PubMed  Google Scholar 

  16. 16

    Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nat. Cell Biol. 11, 123–132 (2009).

    CAS  PubMed  Google Scholar 

  17. 17

    Iwai, K. & Tokunaga, F. Linear polyubiquitination: a new regulator of NF-κB activation. EMBO Rep. 10, 706–713 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Vissers, L.E., Veltman, J.A., van Kessel, A.G. & Brunner, H.G. Identification of disease genes by whole genome CGH arrays. Hum. Mol. Genet. 14, R215–R223 (2005).

    CAS  PubMed  Google Scholar 

  19. 19

    Byun, M. et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207, 2307–2312 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Bolze, A. et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am. J. Hum. Genet. 87, 873–881 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kirisako, T. et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 25, 4877–4887 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637–641 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).

    CAS  PubMed  Google Scholar 

  24. 24

    Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).

    CAS  PubMed  Google Scholar 

  25. 25

    Tatematsu, K. et al. Transcriptional activity of RBCK1 protein (RBCC protein interacting with PKC 1): requirement of RING-finger and B-Box motifs and regulation by protein kinases. Biochem. Biophys. Res. Commun. 247, 392–396 (1998).

    CAS  PubMed  Google Scholar 

  26. 26

    Tian, Y. et al. RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-κB activation by targeting TAB2/3 for degradation. J. Biol. Chem. 282, 16776–16782 (2007).

    CAS  PubMed  Google Scholar 

  27. 27

    Haas, T.L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).

    CAS  PubMed  Google Scholar 

  28. 28

    Hostager, B.S., Kashiwada, M., Colgan, J.D. & Rothman, P.B. HOIL-1L interacting protein (HOIP) is essential for CD40 signaling. PLoS ONE 6, e23061 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Zak, D.E. et al. Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. Proc. Natl. Acad. Sci. USA 108, 11536–11541 (2011).

    CAS  PubMed  Google Scholar 

  30. 30

    Picard, C., Puel, A., Bustamante, J., Ku, C.L. & Casanova, J.L. Primary immunodeficiencies associated with pneumococcal disease. Curr. Opin. Allergy Clin. Immunol. 3, 451–459 (2003).

    PubMed  Google Scholar 

  31. 31

    Seymour, R.E. et al. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 8, 416–421 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    HogenEsch, H., Janke, S., Boggess, D. & Sundberg, J.P. Absence of Peyer's patches and abnormal lymphoid architecture in chronic proliferative dermatitis (cpdm/cpdm) mice. J. Immunol. 162, 3890–3896 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    HogenEsch, H. et al. Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12. Eur. J. Immunol. 31, 734–742 (2001).

    CAS  PubMed  Google Scholar 

  34. 34

    Liang, Y., Seymour, R.E. & Sundberg, J.P. Inhibition of NF-kappaB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice. J. Invest. Dermatol. 131, 141–149 (2011).

    CAS  PubMed  Google Scholar 

  35. 35

    Moses, S.W. & Parvari, R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr. Mol. Med. 2, 177–188 (2002).

    CAS  PubMed  Google Scholar 

  36. 36

    Bruno, C. et al. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 63, 1053–1058 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Pellissier, J.F., de Barsy, T., Bille, J., Serratrice, G. & Toga, M. Polysaccharide (amylopectin-like) storage myopathy histochemical ultrastructural and biochemical studies. Acta Neuropathol. Suppl. 7, 292–296 (1981).

    CAS  PubMed  Google Scholar 

  38. 38

    Ewert, R. et al. [Glycogenosis type IV as a rare cause of cardiomyopathy—report of a successful heart transplantation.] Z. Kardiol. 88, 850–856 (1999).

    CAS  PubMed  Google Scholar 

  39. 39

    Vernia, S., Rubio, T., Heredia, M., Rodriguez de Cordoba, S. & Sanz, P. Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS ONE 4, e5907 (2009).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Lesca, G. et al. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia 51, 1691–1698 (2010).

    CAS  PubMed  Google Scholar 

  41. 41

    Monaghan, T.S. & Delanty, N. Lafora disease: epidemiology, pathophysiology and management. CNS Drugs 24, 549–561 (2010).

    CAS  PubMed  Google Scholar 

  42. 42

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Smahi, A. et al. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405, 466–472 (2000).

    CAS  PubMed  Google Scholar 

  46. 46

    Chaussabel, D. et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29, 150–164 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


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




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.

Corresponding author

Correspondence to Jean-Laurent Casanova.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–7 (PDF 3850 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Boisson, B., Laplantine, E., Prando, C. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13, 1178–1186 (2012).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing