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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Amino Acid Sequence
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Animals
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Base Sequence
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Child
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Cytidine Deaminase / genetics
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Cytidine Deaminase / immunology*
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DNA Glycosylases*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Humans
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Immune Complex Diseases / genetics*
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Immune Complex Diseases / immunology
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Immunoglobulin Class Switching / genetics*
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Immunoglobulin Class Switching / immunology
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Immunoglobulin M / genetics
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Immunoglobulin M / immunology
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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N-Glycosyl Hydrolases / biosynthesis
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N-Glycosyl Hydrolases / deficiency*
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N-Glycosyl Hydrolases / genetics
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N-Glycosyl Hydrolases / immunology
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Point Mutation
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Analysis, DNA
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Somatic Hypermutation, Immunoglobulin / genetics*
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Somatic Hypermutation, Immunoglobulin / immunology
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Uracil-DNA Glycosidase
Substances
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Immunoglobulin M
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RNA, Messenger
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DNA Glycosylases
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N-Glycosyl Hydrolases
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Uracil-DNA Glycosidase
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase
Associated data
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GENBANK/X99018
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GENBANK/Y08975
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RefSeq/NM_003362
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RefSeq/NM_080911