Abstract
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.
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Acknowledgements
We thank O. Hermine (Paris, France) and M. Endou (Iwate, Japan) for referral of patients. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer, la Ligue Contre le Cancer, the European Economic Community (contract QLG1-CT- 2001-01536- IMPAD), the Research Council of Norway, the Norwegian Cancer Association, the Svanhild and Arne Must Fund for Medical Research and the Louis Jeantet Foundation, and by grants from the National Institutes of Health (HD 17427-33), the March of Dimes Birth Defects Foundation (96-0330), the Immunodeficiency Foundation and the Jeffrey-Modell Foundation. P.R. is a scientist from Centre National de la Recherche Scientifique (Paris, France). N.C. is supported by the Association pour la Recherche sur le Cancer.
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Imai, K., Slupphaug, G., Lee, WI. et al. Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4, 1023–1028 (2003). https://doi.org/10.1038/ni974
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DOI: https://doi.org/10.1038/ni974
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