title: Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 429, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Nadia
authors.initials: N
authors.lastname: Catalan
authors.forename: Leman
authors.initials: L
authors.lastname: Yel
authors.forename: Monique
authors.initials: M
authors.lastname: Forveille
authors.forename: Bodil
authors.initials: B
authors.lastname: Kavli
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D045647:DNA Glycosylases; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007105:Immune Complex Diseases / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000276:immunology; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007075:Immunoglobulin M; D012333:RNA, Messenger; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase