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* Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892;
Clinica Pediatrica and Istituto di Medicina, Molecolare "Angelo Nocivelli," Università di Brescia, Brescia, Italy;
Institut National de la Santé de la Recherche Médicale, Unité 768, Paris, France;
Université Paris-Descartes, Faculté de Médicine René Descartes, Paris, France; and
¶ Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Service d’Immunologie et d’Hématologie Pédiatrique, Paris, France
Somatic hypermutation (SHM) of Ig genes depends upon the deamination of C nucleotides in WRCY (W = A/T, R = A/G, Y = C/T) motifs by activation-induced cytidine deaminase (AICDA). Despite this, a large number of mutations occur in WA motifs that can be accounted for by the activity of polymerase 
(POL ). To determine whether there are AICDA-independent mutations and to characterize the relationship between AICDA- and POL -mediated mutations, 1470 H chain and 1313 
- and 
-chain rearrangements from three AICDA–/– patients were analyzed. The Ig mutation frequency of all VH genes from AICDA–/– patients was 40-fold less than that of normal donors, whereas the mutation frequency of mutated VH sequences from AICDA–/– patients was 6.8-fold less than that of normal donors. AICDA–/– B cells lack mutations in WRCY/RGYW motifs as well as replacement mutations and mutational targeting in complementarity-determining regions. A significantly reduced mutation frequency in WA motifs compared with normal donors and an increased percentage of transitions, which may relate to reduced uracil DNA-glycosylase activity, suggest a role for AICDA in regulating POL and uracil DNA-glycosylase activity. Similar results were observed in VL rearrangements. The residual mutations were predominantly G:C substitutions, indicating that AICDA-independent cytidine deamination was a likely, yet inefficient, mechanism for mutating Ig genes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Intramural Research Program, grants from the Institut National de la Santé et de la Recherche Médicale, Association de la Recherche Contre le Cancer, the European Community No. PL 006411 (EUROPOLICY-PID)-6th Programme Cadre de Recherche Développment, the Association Nationale pour la Recherche, Institut National du Cancer, and a grant from the Fondazione C. Golgi and the Associazione Immunodeficienze Primitive, Brescia, Italy.
2 Address correspondence and reprint requests to Dr. Peter E. Lipsky, National Institute of Arthritis and Musculoskeletal and Skin Diseases, 9000 Rockville Pike, Building 10, 6D47C, Bethesda, MD 20892. E-mail address: lipskyp{at}mail.nih.gov
3 Abbreviations used in this paper: AICDA, activation-induced cytidine deaminase; FR, framework region; MMR, mismatch repair; POL, polymerase; R, replacement; S, silent; SHM, somatic hypermutation; GC, germinal center; UNG, uracil-DNA glycosylase.
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