Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination
Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination
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DOI：
10.1172/jci41305
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Cortes, Patricia
中科院分区：
文献类型：
--
作者：
Couedel, Chrystelle;Roman, Christopher;Cortes, Patricia
Rag 2在抗原受体的产生中起重要作用。损害Rag 2功能的突变可导致严重联合免疫缺陷（SCID），一种以T和B细胞完全缺失为特征的病症，或Omenn综合征（OS），一种以B细胞几乎缺失和寡克隆自身反应性T细胞存在为特征的SCID形式。在这里，我们提出了一组突变的比较研究，这些突变是在SCID或OS患者的Rag 2的非经典植物同源域（PHD）中鉴定的。我们表明，PHD突变小鼠Rag 2蛋白，对应于这些患者中发现的那些蛋白，极大地损害了Rag 2缺陷型pro-B细胞系中IG基因片段的内源性重组，这与蛋白稳定性降低有关，核定位受损和/或Rag 2与核心组蛋白之间的相互作用丧失。我们的研究结果表明，点突变的Rag 2的PHD妥协的功能，整个蛋白质，从而解释了为什么细胞表达PHD点突变体的表型不同于那些表达核心Rag 2蛋白，缺乏整个C-末端区域，因此缺乏的调节所施加的PHD。总之，我们的研究结果揭示了PHD Rag 2突变的各种有害影响，并证明了该结构域在调节抗原受体基因组装中的关键作用。我们相信这些结果揭示了SCID和OS免疫缺陷的新机制。
Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition characterized by complete absence of T and B cells, or Omenn syndrome (OS), a form of SCID characterized by the virtual absence of B cells and the presence of oligoclonal autoreactive T cells. Here, we present a comparative study of a panel of mutations that were identified in the noncanonical plant homeodomain (PHD) of Rag2 in patients with SCID or OS. We show that PHD mutant mouse Rag2 proteins that correspond to those found in these patients greatly impaired endogenous recombination of Ig gene segments in a Rag2-deficient pro-B cell line and that this correlated with decreased protein stability, impaired nuclear localization, and/or loss of the interaction between Rag2 and core histones. Our results demonstrate that point mutations in the PHD of Rag2 compromise the functionality of the entire protein, thus explaining why the phenotype of cells expressing PHD point mutants differs from those expressing core Rag2 protein that lacks the entire C-terminal region and is therefore devoid of the regulation imposed by the PHD. Together, our findings reveal the various deleterious effects of PHD Rag2 mutations and demonstrate the crucial role of this domain in regulating antigen receptor gene assembly. We believe these results reveal new mechanisms of immunodeficiency in SCID and OS.