title: A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors.
abstract: Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rbeta1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL-12Rbeta1. These 6 exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Five of 6 monoclonal anti-IL-12Rbeta1 antibodies tested recognized the internally truncated chain on the cell surface. However, IL-12 and IL-23 did not bind normally to the patient's IL-12Rbeta1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon-gamma (IFN-gamma) production was not induced in the patient's cells upon stimulation with even high doses of IL-12 or IL-23. The functional defect was completely rescued by retrovirus-mediated IL-12Rbeta1 gene transfer. Thus, the detection of IL-12Rbeta1 on the cell surface does not exclude the possibility of complete IL-12Rbeta1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12Rbeta1, defining a novel genetic form of IL-12Rbeta1 deficiency.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes (Institut National de la Santé et de la Recherche Médicale U550), Paris, France, EU.
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Orchidée Filipe
authors.initials: OF
authors.lastname: Santos
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Jacov
authors.initials: J
authors.lastname: Levy
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons; D005434:Flow Cytometry; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D016366:Open Reading Frames; D010641:Phenotype; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D018123:Receptors, Interleukin / Q000172:deficiency / Q000378:metabolism*; D053707:Receptors, Interleukin-12; D012190:Retroviridae / Q000235:genetics; D050797:STAT4 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C508438:IL12RB1 protein, human; C508840:IL23A protein, human; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D012313:RNA; D007371:Interferon-gamma