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The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-γ receptor 1 and has a dominant-negative effect on interferon-γ signal transduction
  1. Satoshi Okada (s-okada{at}pg8.so-net.ne.jp)
  1. Hiroshima University, Japan
    1. Nobutsune Ishikawa
    1. Hiroshima University, Japan
      1. Kenfichiro Shirao
      1. Hiroshima University, Japan
        1. Hiroshi Kawaguchi, M.D.
        1. Hiroshima University, Japan
          1. Miyuki Tsumura
          1. Hiroshima University, Japan
            1. Yoshinori Ohno
            1. Hiroshima University, Japan
              1. Shinfichiro Yasunaga
              1. Hiroshima University, Japan
                1. Motoaki Ohtsubo
                1. Hiroshima University, Japan
                  1. Yoshihiro Takihara
                  1. Hiroshima University, Japan
                    1. Masao Kobayashi (masak{at}hiroshima-u.ac.jp)
                    1. Hiroshima University, Japan

                      Abstract

                      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
                      • IFNGR1
                      • Mycobacterium
                      • congenital Immunodeficiency
                      • osteomyelitis

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