Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow
Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow
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DOI：
10.1182/blood-2002-01-0187
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发表时间：
2003-02-15
期刊：
影响因子：
20.3
通讯作者：
van Dongen, JJM
中科院分区：
文献类型：
--
作者：
Noordzij, JG;Verkaik, NS;van Dongen, JJM
严重联合免疫缺陷病（SCID）可以根据T、B和自然杀伤（NK）细胞的缺失或存在进行免疫学分类。约30%的T-B-NK+ SCID患者携带重组激活基因（RAG）突变。一些没有RAG基因突变的T-B-NK+ SCID患者对电离辐射敏感，其中一些放射敏感（RS） SCID患者最近显示Artemis基因有大量缺失或截断突变，这意味着Artemis在DNA双链断裂（dsb）修复中起作用。我们发现5例RS-SCID患者没有RAG基因突变，其中4例有Artemis基因突变。一名患者有一个大的基因组缺失，但其他3名患者在Artemis蛋白SNM1同源结构域的保守氨基酸残基上携带简单的错义突变。染色体外V(D)J重组实验显示，这些患者的成纤维细胞形成正常和精确的信号关节，但编码关节形成效率低下，这可能是野生型Artemis基因的补充。含有SNM1同源结构域错义突变的细胞与大量缺失的细胞具有相同的重组表型，表明这些氨基酸残基对于Artemis功能是必不可少的。2例RS-SCID患者骨髓样本的免疫基因分型和免疫表型分析显示，没有完全的V-H-J(H)基因重排，因此在前b细胞受体检查点(即从Cylgmu（-）前b - i细胞过渡到Cylgmu（+）前b - ii细胞时，b细胞分化完全停止。这种抑制的完全性说明了Artemis在淋巴细胞分化的这一阶段的重要性。(C) 2003年由美国血液病学会出版。
Severe combined immunodeficiency disease (SCID) can be immunologically classified by the absence or presence of T, B, and natural killer (NK) cells. About 30% of T-B-NK+ SCID patients carry mutations in the recombination activating genes (RAG). Some T-B-NK+ SCID patients without RAG gene mutations are sensitive to ionizing radiation, and several of these radiosensitive (RS) SCID patients were recently shown to have large deletions or truncation mutations in the Artemis gene, implying a role for Artemis in DNA double-strand break (dsb) repair. We identified 5 RS-SCID patients without RAG gene mutations, 4 of them with Artemis gene mutations. One patient had a large genomic deletion, but the other 3 patients carried simple missense mutations in conserved amino acid residues in the SNM1 homology domain of the Artemis protein. Extrachromosomal V(D)J recombination assays showed normal and precise signal joint formation, but inefficient coding joint formation in fibroblasts of these patients, which could be complemented by the wild-type Artemis gene. The cells containing the missense mutations in the SNM1 homology domain had the same recombination phenotype as the cells with the large deletion, indicating that these amino acid residues are indispensable for Artemis function. Immunogenotyping and immunophenotyping of bone marrow samples of 2 RS-SCID patients showed the absence of complete V-H-J(H) gene rearrangements and consequently a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint-that is, at the transition from Cylgmu(-) pre-B-I cells to Cylgmu(+) pre-B-II cells. The completeness of this arrest illustrates the importance of Artemis at this stage of lymphoid differentiation. (C) 2003 by The American Society of Hematology.