机构:
NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USANIAMSD, Autoimmun Branch, Bethesda, MD 20892 USA
Russ, Daniel E.
[2
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Jima, Dereje D.
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机构:
Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USANIAMSD, Autoimmun Branch, Bethesda, MD 20892 USA
Jima, Dereje D.
[3
]
Dave, Sandeep S.
论文数: 0引用数: 0
h-index: 0
机构:
Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA
Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USANIAMSD, Autoimmun Branch, Bethesda, MD 20892 USA
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)