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Article
Nature Immunology  4, 1023 - 1028 (2003)
Published online: 7 September 2003; | doi:10.1038/ni974

Human uracil−DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination

Kohsuke Imai1, Geir Slupphaug2, Wen-I Lee3, 4, Patrick Revy1, Shigeaki Nonoyama5, Nadia Catalan1, Leman Yel6, Monique Forveille1, Bodil Kavli2, Hans E Krokan2, Hans D Ochs3, Alain Fischer1, 7 & Anne Durandy1

1  Institut National de la Santé et de la Recherche Médicale Unité 429, Hôpital Necker-Enfants Malades, 75015 Paris, France.

2  Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.

3  Department of Pediatrics, University of Washington, Seattle, Washington 98195-6320, USA.

4  Department of Pediatrics, Chang Gung Children's Hospital and University, 333, Taoyuan, Taiwan, China.

5  Department of Pediatrics, National Defense Medical College, 359-8513, Saitama, Japan.

6  Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, California 92697, USA.

7  Unité d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.

Correspondence should be addressed to Anne Durandy durandy@necker.fr
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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Nature Immunology
ISSN: 1529-2908
EISSN: 1529-2916
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