In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ
Emmanuelle Jouanguy, … , Yildiz Camcioglu, Jean-Laurent Casanova
Emmanuelle Jouanguy, … , Yildiz Camcioglu, Jean-Laurent Casanova
Published May 15, 2000
Citation Information: J Clin Invest. 2000;105(10):1429-1436. https://doi.org/10.1172/JCI9166.
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In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ

Abstract

Complete IFN-γ receptor ligand-binding chain (IFNγR1) 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 IFNγR1 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 IFNγR1-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 125I–IFN-γ to cells was observed in any patient, however, and the cells failed to respond to IFN-γ. The mutations therefore cause complete IFNγR1 deficiency by disrupting the IFN-γ–binding site without affecting surface expression. The detection of surface IFNγR1 molecules by specific antibodies, including blocking antibodies, does not exclude a diagnosis of complete IFNγR1 deficiency.

Authors

Emmanuelle Jouanguy, Stéphanie Dupuis, Annaïck Pallier, Rainer Döffinger, Marie-Claude Fondanèche, Claire Fieschi, Salma Lamhamedi-Cherradi, Frédéric Altare, Jean-François Emile, Patrick Lutz, Pierre Bordigoni, Haluk Cokugras, Necla Akcakaya, Judith Landman-Parker, Jean Donnadieu, Yildiz Camcioglu, Jean-Laurent Casanova

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Figure 1

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A novel type of mutation in the IFNGR1 gene. The IFNGR1 gene-coding regi...
A novel type of mutation in the IFNGR1 gene. The IFNGR1 gene-coding region is indicated with vertical bars separating the exons, designated by roman numerals. Mutations in red (nonsense and splice mutations and frameshift insertions and deletions; recessive) have been reported elsewhere and cause complete IFNγR1 deficiency with no detectable expression of IFNγR1 at the cell surface. Mutations in purple (I87T, recessive) and green (818delT and 818del4, dominant) have also been reported elsewhere and cause partial, as opposed to complete, IFNγR1 deficiency. Mutations in blue (missense mutations and in-frame deletions; recessive) are reported in this study and cause complete IFNγR1 deficiency with detectable surface expression of IFNγR1.