Journal
JOURNAL OF MEDICAL GENETICS
Volume 44, Issue 8, Pages 485-491Publisher
B M J PUBLISHING GROUP
DOI: 10.1136/jmg.2007.049635
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Background: Patients with interferon-gamma receptor 1 ( IFN gamma R1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFN gamma R1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFN gamma R1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFN gamma R1. 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 gamma signal transduction, the underlying molecular mechanism is unresolved. Objective: We characterised the 774del4 mutant of IFN gamma R1 using a gene-expression system to examine the effects of this mutation on IFN gamma signal transduction. Results: We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFN gamma R1 in a patient with recurrent mycobacterial infections. IFN gamma R1 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 gamma was partially deficient. We expressed two truncated forms of IFN gamma R1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFN gamma R1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFN gamma signal transduction. Conclusion: Like the 818del4 mutation, 774del4 produces a truncated form of IFN gamma R1, which has a dominant-negative effect on IFN gamma signal transduction through altered receptor stability.
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