Human HOIP and LUBAC de!ciency underlies autoin"ammation, immunode!ciency, amylopectinosis, and lymphangiectasia

pectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoin"ammation, combined immunode!ciency, 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-KB activation are impaired in the patient’s !broblasts stimulated by IL- 1B or TNF. In contrast, the patient’s monocytes respond to IL-1B 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-de!cient patients. Clinical differences between HOIL- 1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our !ndings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing in"ammation and immunity in both hematopoietic and nonhematopoietic cells.