Okada Satoshi, Ishikawa Nobutsune, Shirao Ken'ichiro, Kawaguchi Hiroshi, Tsumura Miyuki, Ohno Yoshinori, Yasunaga Shin'ichiro, Ohtsubo Motoaki, Takihara Yoshihiro, Kobayashi Masao
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
J Med Genet. 2007 Aug;44(8):485-91. doi: 10.1136/jmg.2007.049635. Epub 2007 May 18.
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.
干扰素-γ受体1（IFNγR1）缺陷患者对细胞内病原体如分枝杆菌表现出选择性易感性。IFNγR1缺陷是一种遗传性免疫缺陷疾病，可为隐性或显性。已知显性形式的IFNγR1缺陷与在IFNγR1细胞内结构域引入过早终止密码子的突变有关。一种这样的突变，818del4，被认为是最常见的类型。尽管这些突变被推测对IFNγ信号转导发挥显性负性作用，但其潜在的分子机制尚未明确。
我们使用基因表达系统对IFNγR1的774del4突变体进行了表征，以研究该突变对IFNγ信号转导的影响。
我们在一名复发性分枝杆菌感染患者中鉴定出IFNGR1中的一种新的显性突变，命名为774del4，其产生了截短形式的IFNγR1。IFNγR1在该患者外周血CD14阳性细胞表面过度表达，并且对高剂量IFNγ的反应中STAT1磷酸化部分缺陷。我们通过瞬时转染在HEK 293细胞中表达了两种截短形式的IFNγR1，774del4和818del4，发现这些突变体由于受体稳定性受损而在细胞表面过度表达IFNγR1，这导致对IFNγ信号转导产生显性负性作用。
与818del4突变一样，774del4产生截短形式的IFNγR1，其通过改变受体稳定性对IFNγ信号转导产生显性负性作用。
