Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis

Thilo Jakob*, Gabriele V. Köllisch, Maike Howaldt, Mayte Bewersdorff, Birgit Rathkolb, Marcel L. Müller, Nadja Sandholzer, Lars Nitschke, Matthias Schiemann, Martin Mempel, Markus Ollert, Antonie Neubauer, Dian A. Soewarto, Elisabeth Kremmer, Johannes Ring, Heidrun Behrendt, Heinrich Flaswinkel

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)


Background: Primary cellular immunodeficiencies are a group of genetic disorders in which 1 or more components of the cellular immune system are lacking or dysfunctional. Objective: We sought to identify novel mouse mutants that display primary cellular immunodeficiencies. Methods: Genome-wide N-ethyl-N-nitrosourea mutagenesis was performed in mice, followed by a phenotype screen of immunologic blood parameters. Results: We identified novel mouse mutants with isolated B-cell deficiency, combined block in early B- and T-cell development, combined T-cell and natural killer cell reduction, and 3 different forms of T-cell deficiencies. One of the mutants, designated ΔT3, displayed a combined phenotype of increased IgE, absence of peripheral T cells, and block in late thymocyte differentiation. In addition, ΔT3 mice were unable to mount specific humoral immune responses. Chromosomal mapping and sequencing of candidate genes revealed a novel point mutation in the kinase domain of the T-cell receptor ζ chain-associated protein kinase (Zap70). In contrast to Zap70-deficient mice, ΔT3 mutants displayed normal Zap70 mRNA and residual Zap70 protein levels. Complementation studies with Zap70-deficient mice confirmed that the point mutation found in Zap70 was causative for the ΔT3 phenotype, including increased IgE plasma levels, a phenotype that has not been associated with altered Zap70 function in the past. Conclusion: Random genome-wide mutagenesis combined with a phenotype screen can be used to generate novel mouse mutants with primary cellular immunodeficiencies.

Original languageEnglish
Pages (from-to)179-184.e7
JournalJournal of Allergy and Clinical Immunology
Issue number1
Publication statusPublished - Jan 2008
Externally publishedYes


  • IgE
  • N-ethyl-N-nitrosourea mutagenesis
  • Zap70
  • immunodeficiency
  • rodents


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