Background: Patients with interferon-γ receptor 1 (IFN-γR1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFN-γR1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFN-γR1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFN-γR1. One such mutation, 818del4, is believed to be the most common type. Although these mutations are presumed to exert a dominant-negative effect on IFN-γ signal transduction, the actual molecular mechanism is unresolved.
Objective: We characterized the 774del4 mutant of IFN-γR1 using a gene expression system to examine the effects of this mutation on IFN-γ signal transduction.
Results: We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFN-γR1 in a patient with recurrent mycobacterial infections. IFN-γR1 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 IFN-γ was partially deficient. We expressed two truncated forms of IFN-γR1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFN-γR1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFN-γ signal transduction.
Conclusion: Like the 818del4 mutation, 774del4 produces a truncated form of IFN-γR1, which has a dominant-negative effect on IFN-γ signal transduction through altered receptor stability.
- IFN-gamma receptor 1
- congenital Immunodeficiency
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