Structural and functional basis for JAK3-deficient severe combined immunodeficiency
Structural and functional basis for JAK3-deficient severe combined immunodeficiency
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DOI：
10.1182/blood.v90.10.3996
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发表时间：
1997-11-15
期刊：
影响因子：
20.3
通讯作者：
Villa, A
中科院分区：
文献类型：
--
作者：
Candotti, F;Oakes, SA;Villa, A
Janus家族激酶JAK3的突变已被发现是人类常染色体隐性严重联合免疫缺陷（SCID）的原因。我们在此报告了4例新的无关联的jak3缺陷SCID患者的分析。遗传缺陷是异质性的，包括大量的基因内缺失和不同的点突变，导致错义替换，早期终止密码子或剪接缺陷。我们对从这些患者身上获得的淋巴母细胞样b细胞系进行了一系列细胞因子诱导的生化事件研究。JAK3酪氨酸磷酸化对白细胞介素-9 （IL-2）和IL-4的反应在所有患者中都存在异常。因此，il -2介导的STATE磷酸化也不存在或几乎检测不到。相反，在所有情况下，我们都可以显示IL-4刺激下STATE的磷酸化减少但明显。在一名携带JAK3 JH3结构域单个氨基酸变化（Glu481Gly）的患者中，我们观察到部分保守的IL-2反应导致JAK3和STAT5磷酸化水平降低，但可检测到。有趣的是，携带这种突变的患者产生了大量循环CD4(+)/CD45RO（+）活化的T淋巴细胞，这些T淋巴细胞功能受损。在两个病例中，患者细胞表达了JH2伪激酶结构域突变的JAK3蛋白。该区域的单半胱氨酸到精氨酸取代（Cys759Arg）导致构成型JAK3酪氨酸磷酸化的高基础水平，对血清饥饿下调或细胞因子介导的上调均无反应。这些JAK3缺陷患者的遗传缺陷和生化异常的特征将有助于确定JAK3在免疫系统个体发育中的作用，并可能导致对JAK3功能域的更好理解。(C) 1997年由美国血液病学会出版。
Mutations of the Janus family kinase JAK3 have been found to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans. We report here the analysis of four new unrelated patients affected by JAK3-deficient SCID. The genetic defects were heterogeneous and included a large intragenic deletion as well as different point mutations, leading to missense substitutions, early stop codons, or splicing defects. We performed a series of studies of the biochemical events induced by cytokines on lymphoblastoid B-cell lines obtained from these patients. Abnormalities in tyrosine phosphorylation of JAK3 in response to interleukin-9 (IL-2) and IL-4 were present in all patients. Accordingly, IL-2-mediated phosphorylation of STATE was also absent or barely detectable. On the contrary, in all cases, we could show reduced but clear phosphorylation of STATE upon IL-4 stimulation. In one patient carrying a single amino acid change (Glu481Gly) in the JH3 domain of JAK3, we observed partially conserved IL-2 responses resulting in reduced but detectable levels of JAK3 and STAT5 phosphorylation. Interestingly, the patient bearing this mutation developed a substantial number of circulating CD4(+)/CD45RO(+) activated T lymphocytes that were functionally impaired. In two cases, patients' cells expressed JAK3 proteins with mutations in the JH2 pseudo-kinase domain. A single cysteine to arginine substitution (Cys759Arg) in this region resulted in high basal levels of constitutive JAK3 tyrosine phosphorylation unresponsive to either downregulation by serum starvation or cytokine-mediated upregulation. The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains. (C) 1997 by The American Society of Hematology.