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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.
AuthorsCarin I M Dahlberg, Minghui He, Torkild Visnes, Magda Liz Torres, Elena M Cortizas, Ramiro E Verdun, Lisa S Westerberg, Eva Severinson, Lena Ström
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 9 Pg. 4732-8 (Nov 01 2014) ISSN: 1550-6606 [Electronic] United States
PMID25252954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 by The American Association of Immunologists, Inc.
Chemical References
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
Topics
  • Animals
  • B-Lymphocyte Subsets (immunology, metabolism)
  • Cytidine Deaminase (genetics, metabolism)
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Female
  • Germinal Center (immunology)
  • Hyper-IgM Immunodeficiency Syndrome (genetics, immunology, metabolism)
  • Immunoglobulin Class Switching (genetics, immunology)
  • Immunophenotyping
  • Inheritance Patterns
  • Lymphocyte Count
  • Male
  • Mice
  • Mutation
  • Pedigree
  • Phenotype
  • Quantitative Trait, Heritable
  • Somatic Hypermutation, Immunoglobulin

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