Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination
Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination
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DOI：
10.1038/ni974
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发表时间：
2003-10-01
影响因子：
30.5
通讯作者：
Durandy, A
中科院分区：
文献类型：
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作者：
Imai, K;Slupphaug, G;Durandy, A
活化诱导的胞苷脱氨酶（AID）是免疫球蛋白（IG）类别转换重组（CSR）和体细胞超突变（SHM）产生中的“主分子”，AID缺陷与人类和小鼠中的高IgM表型相关。我们发现尿嘧啶-DNA糖基化酶（UNG）编码基因的隐性突变与CSR在DNA预切割步骤中的严重损害以及3例高IgM综合征患者的SHM模式的部分干扰相关。连同在活化的B细胞中诱导核UNG表达的发现，这些数据支持CSR和SHM的模型，其中AID将靶向DNA（免疫球蛋白开关或可变区）中的胞嘧啶脱氨基为尿嘧啶，随后通过UNG去除尿嘧啶。
Activation-induced cytidine deaminase (AID) is a 'master molecule' in immunoglobulin (Ig) class-switch recombination (CSR) and somatic hypermutation (SHM) generation, AID deficiencies are associated with hyper-IgM phenotypes in humans and mice. We show here that recessive mutations of the gene encoding uracil-DNA glycosylase (UNG) are associated with profound impairment in CSR at a DNA precleavage step and with a partial disturbance of the SHM pattern in three patients with hyper-IgM syndrome. Together with the finding that nuclear UNG expression was induced in activated B cells, these data support a model of CSR and SHM in which AID deaminates cytosine into uracil in targeted DNA (immunoglobulin switch or variable regions), followed by uracil removal by UNG.