Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia

Bertrand Boisson, Emmanuel Laplantine, Kerry Dobbs, Aurélie Cobat, Nadine Tarantino, Melissa Hazen, Hart G.W. Lidov, Gregory Hopkins, Likun Du, Abdelaziz Belkadi, Maya Chrabieh, Yuval Itan, Capucine Picard, Jean Christophe Fournet, Hermann Eibel, Erdyni Tsitsikov, Sung Yun Pai, Laurent Abel, Waleed Al-Herz, Jean Laurent CasanovaAlain Israel, Luigi D. Notarangelo

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87 Citations (Scopus)


Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF-κB activation are impaired in the patient's fibroblasts stimulated by IL-1β or TNF. In contrast, the patient's monocytes respond to IL-1β more vigorously than control monocytes. However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1-and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells.

Original languageEnglish
Pages (from-to)939-951
Number of pages13
JournalJournal of Experimental Medicine
Issue number6
Publication statusPublished - 1 Jan 2015
Externally publishedYes


ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Boisson, B., Laplantine, E., Dobbs, K., Cobat, A., Tarantino, N., Hazen, M., Lidov, H. G. W., Hopkins, G., Du, L., Belkadi, A., Chrabieh, M., Itan, Y., Picard, C., Fournet, J. C., Eibel, H., Tsitsikov, E., Pai, S. Y., Abel, L., Al-Herz, W., ... Notarangelo, L. D. (2015). Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. Journal of Experimental Medicine, 212(6), 939-951.