- 作者：Thilo Jakob ; Gabriele V. Kö ; llisch ; Maike Howaldt ; Mayte Bewersdorff ; Birgit Rathkolb ; Marcel L. Mü ; ller ; Nadja S ; holzer ; Lars Nitschke ; Matthias Schiemann ; Martin Mempel ; Markus Ollert ; Antonie Neubauer ; Dian A. Soewarto ; Elisabeth Kremmer ; Johannes Ring ; Heidrun Behrendt ; Heinrich Flaswink
- 关键词：N-ethyl-N-nitrosourea mutagenesis ; immunodeficiency ; Zap70 ; IgE ; rodents
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2008
- 出版时间：January 2008
- 年：2008
- 卷：121
- 期：1
- 页码：179-184.e7
- 全文大小：905 K
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.