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* Division of Clinical Immunology, IMPI, Karolinska Institute at Huddinge Hospital, Stockholm, Sweden; and Center for Biotechnology and Center for Oral Biology, NOVUM, Huddinge, Sweden;
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden;
Department of Pathology, University of California School of Medicine, Los Angeles, CA 90095; and
Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway
Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes that share common key factors such as activation-induced cytidine deaminase. We have previously shown a role for ATM (mutated in ataxia-telangiectasia) in CSR. In this paper we show that the frequency, distribution, and nature of base pair substitutions in the Ig variable (V) heavy chain genes in ataxia-telangiectasia patients are largely similar to those in normal donors, suggesting a normal SHM process. Characterization of the third complementarity-determining region in B cells from ataxia-telangiectasia patients also shows a normal V(D)J recombination process. SHM-like mutations could be identified in the switch (S) µ region (up to several hundred base pairs upstream of the Sµ-S
breakpoints) in normal in vivo switched human B cells. In the absence of ATM, mutations can still be found in this region, but at less than half the frequency of that in normal donors. The latter mutations are mainly due to transitions (86% compared with 58% in controls) and are biased to A or T nucleotides. An ATM-dependent mechanism, different from that generating SHM in V genes, is therefore likely to be involved in introducing SHM-like mutations in the S region. ATM may thus be one of the factors that is not shared by the CSR and SHM processes.
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