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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
Language english
Publication Year 2008
HGF-reported in Year 2008
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)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health


30201 - Metabolic Health
Research field(s) Immune Response and Infection


Genetics and Epidemiology
PSP Element(s) G-520100-001
G-521200-001
FE 73991
G-501700-003
G-500600-003
DOI 10.1016/j.jaci.2007.07.018
Scopus ID 38149123216
Erfassungsdatum 2008-10-15
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