title: Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia.
abstract: 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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR 3691, Institut Pasteur, 75724 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Laplantine
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Kerry
authors.initials: K
authors.lastname: Dobbs
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR 3691, Institut Pasteur, 75724 Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Tarantino
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hazen
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Hart G W
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hopkins
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Likun
authors.initials: L
authors.lastname: Du
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.affiliation: University Medical Centre Freiburg, Centre of Chronic Immunodeficiency, 79098 Freiburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Erdyni
authors.initials: E
authors.lastname: Tsitsikov
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Sung-Yun
authors.initials: SY
authors.lastname: Pai
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, 70459 Kuwait City, Kuwait Department of Pediatrics, Kuwait University, 13110 Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Howard Hughes Medical Institute, New York, NY 10065 casanova@rockefeller.edu luigi.notarangelo@childrens.harvard.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR 3691, Institut Pasteur, 75724 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Israel
authors.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute, Harvard University, Boston, MA 02115 casanova@rockefeller.edu luigi.notarangelo@childrens.harvard.edu.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D023201:CD40 Ligand / Q000378:metabolism; D002384:Catalysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D018095:Germ-Line Mutation; D006011:Glycogen Storage Disease Type IV / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000473:pathology; D007249:Inflammation; D008200:Lymphangiectasis / Q000473:pathology; D009000:Monocytes / Q000378:metabolism; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D014157:Transcription Factors; D025801:Ubiquitin; D023201:CD40 Ligand; C504507:RBCK1 protein, human; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases