In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptorsfail to bind IFN-gamma

Complete IFN-gamma receptor ligand-binding chain (IFN gamma R1) deficiency is a life-threatening autosomal recessive immune disorder, Affected childre n invariably die of mycobacterial infection, unless bone marrow transplanta tion 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 tra nsmembrane domain, precluding cell surface expression of the receptors, We report herein two sporadic and two familial cases of a novel form of comple te IFN gamma R1 deficiency in which normal numbers of receptors are detecte d at the cell surface. Two in-frame deletions and two missense IFNGR1 mutat ions were identified in the segment encoding the extracellular ligand-bindi ng domain of the receptor. Eight independent IFN gamma R1-specific mAb's, i ncluding seven blocking antibodies, gave recognition patterns that differed between patients, suggesting that different epitopes were altered by the m utations. No specific binding of I-125-IFN-gamma to cells was observed in a ny patient, however, and the cells failed to respond to IFN-gamma. The muta tions therefore cause complete IFN gamma R1 deficiency by disrupting the IF N-gamma-binding site without affecting surface expression, The detection of surface IFN gamma R1 molecules by specific antibodies, including blocking antibodies, does not exclude a diagnosis of complete IFN gamma R1 deficienc y.