Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting
Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting
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DOI：
10.1182/blood-2008-10-183632
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发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Lipsky, Peter E.
中科院分区：
文献类型：
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作者：
Longo, Nancy S.;Lugar, Patricia L.;Lipsky, Peter E.
X连锁高IgM综合征（X-HIgM）患者的CD 27（+）记忆B细胞频率显著降低，其IG基因具有低水平的体细胞高突变（SHM）。为了分析X-HIgM中SHM的性质，我们对209个非生产性和926个生产性IG重链基因进行了测序。在不进行选择的非生产性重排以及生产性重排中，大多数突变位于靶向RGYW、WRCY、WA或TW基序内（R =嘌呤，Y =嘧啶，W = A或T）。然而，RGYW基序中的高变G的靶向显著减少。此外，与正常相比，转换与颠换的比率显著增加。基因芯片分析表明，SHM中涉及的特定基因，包括激活诱导的胞苷脱氨酶（AICDA）和尿嘧啶-DNA糖基化酶（UNG 2），在正常生发中心（GC）B细胞中上调，但不受CD 40连接诱导。从轻链重排中获得了类似的结果。这些结果表明，在不存在CD 40-CD 154相互作用的情况下，SHM显著减少，特别是RGYW基序中AICDA靶向的G残基的突变沿着通常与UNG 2活性相关的颠换减少。（血。2009; 113：3706-3715）
Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity. (Blood. 2009; 113: 3706-3715)