title: Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency.
abstract: 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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, USA.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Laplantine
authors.forename: Carolina
authors.initials: C
authors.lastname: Prando
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Israelsson
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Laura
authors.initials: L
authors.lastname: Israël
authors.forename: Giraldina
authors.initials: G
authors.lastname: Trevejo-Nunez
authors.forename: Dusan
authors.initials: D
authors.lastname: Bogunovic
authors.forename: Alma-Martina
authors.initials: AM
authors.lastname: Cepika
authors.forename: Donna
authors.initials: D
authors.lastname: MacDuff
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.forename: Marjorie
authors.initials: M
authors.lastname: Hubeau
authors.forename: Fanny
authors.initials: F
authors.lastname: Bajolle
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Evelina
authors.initials: E
authors.lastname: Mazzolari
authors.forename: Donatella
authors.initials: D
authors.lastname: Vairo
authors.forename: Fabrice
authors.initials: F
authors.lastname: Agou
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Xavier
authors.initials: X
authors.lastname: Bossuyt
authors.forename: Caroline
authors.initials: C
authors.lastname: Rambaud
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
mesh_terms: D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006011:Glycogen Storage Disease Type IV / Q000235:genetics*; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D014157:Transcription Factors; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases