Journal of medical genetics

The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-gamma receptor 1 and has a dominant-negative effect on interferon-gamma signal transduction.

PMID 17513528


Patients with interferon-gamma receptor 1 (IFNgammaR1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFNgammaR1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFNgammaR1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFNgammaR1. One such mutation, 818del4, is believed to be the most common type. Although these mutations are presumed to exert a dominant-negative effect on IFNgamma signal transduction, the underlying molecular mechanism is unresolved. We characterised the 774del4 mutant of IFNgammaR1 using a gene-expression system to examine the effects of this mutation on IFNgamma signal transduction. We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFNgammaR1 in a patient with recurrent mycobacterial infections. IFNgammaR1 was overexpressed on the surfaces of CD14-positive cells from the peripheral blood of this patient, and STAT1 phosphorylation in response to high doses of IFNgamma was partially deficient. We expressed two truncated forms of IFNgammaR1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFNgammaR1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFNgamma signal transduction. Like the 818del4 mutation, 774del4 produces a truncated form of IFNgammaR1, which has a dominant-negative effect on IFNgamma signal transduction through altered receptor stability.