Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases
Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases
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DOI：
10.1038/leu.2011.371
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发表时间：
2012-05-01
期刊：
影响因子：
11.4
通讯作者：
Borkhardt, A.
中科院分区：
文献类型：
--
作者：
Linka, R. M.;Risse, S. L.;Borkhardt, A.
本研究的目的是评估IL-2诱导T细胞激酶ITK基因内生殖系突变的临床和功能后果。在EB病毒驱动的淋巴组织增生性疾病（EBV-LPD）患者中，SH 2D 1A和XIAP突变阴性（n = 46），我们确定了两名患者分别具有R29 H或D500 T，F501 L，M503 X突变。人野生型（wt）ITK，但没有一个突变体，能够拯救鼠Itk（-/-）T细胞中有缺陷的钙流。脉冲追踪实验表明，与野生型ITK（107分钟）相比，ITK突变导致蛋白质半衰期从25%降低到69%。野生型ITK的普列克底物蛋白同源结构域最显著地结合磷脂酰肌醇单磷酸（PI（3）P、PI（4）P、PI（5）P），并且较少地结合其双重或三重磷酸化衍生物（PIP 2、PIP 3），在具有ITKR 29 H突变体的患者中显著降低的相互作用。ITK突变分布在整个蛋白质上，包括错义、无义和插入缺失突变，这让人想起其在B细胞中的姐妹激酶布鲁顿酪氨酸激酶中的情况。
The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n = 46), we identified two patients with R29H or D500T, F501L, M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3) P, PI(4) P, PI(5) P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITKR29H mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.