title: In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma.
abstract: Complete IFN-gamma receptor ligand-binding chain (IFNgammaR1) deficiency is a life-threatening autosomal recessive immune disorder. Affected children invariably die of mycobacterial infection, unless bone marrow transplantation is undertaken. Pathogenic IFNGR1 mutations identified to date include nonsense and splice mutations and frameshift deletions and insertions. All result in a premature stop codon upstream from the segment encoding the transmembrane domain, precluding cell surface expression of the receptors. We report herein two sporadic and two familial cases of a novel form of complete IFNgammaR1 deficiency in which normal numbers of receptors are detected at the cell surface. Two in-frame deletions and two missense IFNGR1 mutations were identified in the segment encoding the extracellular ligand-binding domain of the receptor. Eight independent IFNgammaR1-specific mAb's, including seven blocking antibodies, gave recognition patterns that differed between patients, suggesting that different epitopes were altered by the mutations. No specific binding of (125)I-IFN-gamma to cells was observed in any patient, however, and the cells failed to respond to IFN-gamma. The mutations therefore cause complete IFNgammaR1 deficiency by disrupting the IFN-gamma-binding site without affecting surface expression. The detection of surface IFNgammaR1 molecules by specific antibodies, including blocking antibodies, does not exclude a diagnosis of complete IFNgammaR1 deficiency.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Faculté de Médecine Necker, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Jouanguy
authors.forename: S
authors.initials: S
authors.lastname: Dupuis
authors.forename: A
authors.initials: A
authors.lastname: Pallier
authors.forename: R
authors.initials: R
authors.lastname: Döffinger
authors.forename: M C
authors.initials: MC
authors.lastname: Fondanèche
authors.forename: C
authors.initials: C
authors.lastname: Fieschi
authors.forename: S
authors.initials: S
authors.lastname: Lamhamedi-Cherradi
authors.forename: F
authors.initials: F
authors.lastname: Altare
authors.forename: J F
authors.initials: JF
authors.lastname: Emile
authors.forename: P
authors.initials: P
authors.lastname: Lutz
authors.forename: P
authors.initials: P
authors.lastname: Bordigoni
authors.forename: H
authors.initials: H
authors.lastname: Cokugras
authors.forename: N
authors.initials: N
authors.lastname: Akcakaya
authors.forename: J
authors.initials: J
authors.lastname: Landman-Parker
authors.forename: J
authors.initials: J
authors.lastname: Donnadieu
authors.forename: Y
authors.initials: Y
authors.lastname: Camcioglu
authors.forename: J L
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002462:Cell Membrane / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D000096743:Interferon gamma Receptor
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007371:Interferon-gamma; D008024:Ligands; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor