Article Text
Abstract
Background: Patients with interferon-γ receptor 1 (IFNγR1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFNγR1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFNγR1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFNγR1. One such mutation, 818del4, is believed to be the most common type. Although these mutations are presumed to exert a dominant-negative effect on IFNγ signal transduction, the underlying molecular mechanism is unresolved.
Objective: We characterised the 774del4 mutant of IFNγR1 using a gene-expression system to examine the effects of this mutation on IFNγ signal transduction.
Results: We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFNγR1 in a patient with recurrent mycobacterial infections. IFNγR1 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 IFNγ was partially deficient. We expressed two truncated forms of IFNγR1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFNγR1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFNγ signal transduction.
Conclusion: Like the 818del4 mutation, 774del4 produces a truncated form of IFNγR1, which has a dominant-negative effect on IFNγ signal transduction through altered receptor stability.
- APC, antigen-presenting cell
- BCG, bacillus Calmette-Guérin
- FCS, fetal calf serum
- IFNγR1, interferon gamma receptor 1
- LPS, lipopolysaccharide
- M-CSF, macrophage colony-stimulating factor
- MSMD, mendelian susceptibility to mycobacterial diseases
- NTM, non-tuberculosis mycobacterium
- PBMC, peripheral blood mononuclear cell
- STAT1, signal transducer and activator of transcription 1
- TNF, tumour necrosis factor
- WT, wild type
- congenital immunodeficiency
- IFNγ receptor 1
- IFNGR1
- mycobacterium
- osteomyelitis
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- APC, antigen-presenting cell
- BCG, bacillus Calmette-Guérin
- FCS, fetal calf serum
- IFNγR1, interferon gamma receptor 1
- LPS, lipopolysaccharide
- M-CSF, macrophage colony-stimulating factor
- MSMD, mendelian susceptibility to mycobacterial diseases
- NTM, non-tuberculosis mycobacterium
- PBMC, peripheral blood mononuclear cell
- STAT1, signal transducer and activator of transcription 1
- TNF, tumour necrosis factor
- WT, wild type
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Footnotes
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Published Online First 18 May 2007
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This work was supported by a grant-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology and a grant-in-aid from the Japanese Ministry of Health, Labor, and Welfare. The 774del4 mutation of IFNGR1 has been assigned GenBank accession number EF535103.
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Competing interests: None declared.
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