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Jakob, T. ; Köllisch, G.V. ; Howaldt, M.* ; Bewersdorff, M. ; Rathkolb, B.* ; Müller, M.L.* ; Sandholzer, N.* ; Nitschke, L.* ; Schiemann, M. ; Mempel, M. ; Ollert, M.* ; Neubauer, A.* ; Soewarto, D. ; Kremmer, E. ; Ring, J.* ; Behrendt, H. ; Flaswinkel, H.*

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

J. Allergy Clin. Immunol. 121, 179-184 (2008)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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 DeltaT3, displayed a combined phenotype of increased IgE, absence of peripheral T cells, and block in late thymocyte differentiation. In addition, DeltaT3 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 zeta chain-associated protein kinase (Zap70). In contrast to Zap70-deficient mice, DeltaT3 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 DeltaT3 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords N-ethyl-N-nitrosourea mutagenesis; immunodeficiency; Zap70; IgE; rodents
ISSN (print) / ISBN 0091-6749
e-ISSN 1097-6825
Journal The journal of allergy and clinical immunology
Quellenangaben Volume: 121, Issue: 1, Pages: 179-184 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute of Lung Health and Immunity (LHI)
Institute of Epidemiology (EPI)
Institute of Molecular Immunology (IMI)
Institute of Experimental Genetics (IEG)