title: Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2.
abstract: Autosomal recessive form of hyper-IgM syndrome type 2 (AR-HIGM2) is secondary to mutations affecting both alleles of AICDA gene encoding activation-induced cytidine deaminase, characterized by defects of immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) in most of the patients. We herein report the immunological phenotype of seven patients carrying a single heterozygous R190X mutation in AICDA. Variable defect in in vivo CSR inherited as an autosomal dominant (AD) trait strongly suggests that this heterozygous AICDA mutation causes HIGM (AD-HIGM2). In AD-HIGM2 B cells, CSR was consistently found impaired in vitro. However, in contrast to AR-HIGM2, the CSR-induced double-stranded DNA breaks in the switch region of IgM heavy chain gene were detected. The SHM frequency in V regions of IgM heavy chain gene in B cells was normal in all (but one patient). The characteristics of the AD-HIGM2 phenotype indicate that the AID C-terminal region may be involved in DNA repair machinery required for CSR.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 429, Hôpital Necker-Enfants Malades, Paris, France. kimai@ndmc.ac.jp
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D002869:Chromosome Aberrations; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D013577:Syndrome; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007075:Immunoglobulin M; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase; D045643:DNA Repair Enzymes