title: A novel mouse model for the hyper-IgM syndrome: a spontaneous activation-induced cytidine deaminase mutation leading to complete loss of Ig class switching and reduced somatic hypermutation.
abstract: We describe a spontaneously derived mouse line that completely failed to induce Ig class switching in vitro and in vivo. The mice inherited abolished IgG serum titers in a recessive manner caused by a spontaneous G → A transition mutation in codon 112 of the aicda gene, leading to an arginine to histidine replacement (AID(R112H)). Ig class switching was completely reconstituted by expressing wild-type AID. Mice homozygous for AID(R112H) had peripheral B cell hyperplasia and large germinal centers in the absence of Ag challenge. Immunization with SRBCs elicited an Ag-specific IgG1 response in wild-type mice, whereas AID(R112H) mice failed to produce IgG1 and had reduced somatic hypermutation. The phenotype recapitulates the human hyper-IgM (HIGM) syndrome that is caused by point mutations in the orthologous gene in humans, and the AID(R112H) mutation is frequently found in HIGM patients. The AID(R112H) mouse model for HIGM provides a powerful and more precise tool than conventional knockout strategies.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Carin I M
authors.initials: CI
authors.lastname: Dahlberg
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden;
authors.forename: Minghui
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Torkild
authors.initials: T
authors.lastname: Visnes
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Magda Liz
authors.initials: ML
authors.lastname: Torres
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cortizas
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Ramiro E
authors.initials: RE
authors.lastname: Verdun
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; lisa.westerberg@ki.se eva.severinson@su.se lena.strom@ki.se.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden; lisa.westerberg@ki.se eva.severinson@su.se lena.strom@ki.se.
authors.forename: Eva
authors.initials: E
authors.lastname: Severinson
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Lena
authors.initials: L
authors.lastname: Ström
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D018858:Germinal Center / Q000276:immunology; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology*; D016130:Immunophenotyping; D040582:Inheritance Patterns; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D027041:Somatic Hypermutation, Immunoglobulin; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase