Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis - 15/08/11
, Gabriele V. Köllisch, PhD b, Maike Howaldt, PhD c, Mayte Bewersdorff, MSc b, Birgit Rathkolb, PhD c, Marcel L. Müller, MD a, Nadja Sandholzer c, Lars Nitschke, PhD d, Matthias Schiemann, PhD e, f, Martin Mempel, MD b, Markus Ollert, MD g, Antonie Neubauer, PhD h, Dian A. Soewarto, MSc i, Elisabeth Kremmer, MD j, Johannes Ring, MD, PhD k, Heidrun Behrendt, MD b, Heinrich Flaswinkel, PhD c, ⁎ Reprint requests: Thilo Jakob, MD, Professor of Allergy and Immunodermatology, Allergy Research Group, University Medical Center Freiburg, Department of Dermatology, Hauptstr. 7, 79104 Freiburg, Germany.Heinrich Flaswinkel, PhD, Institute of Molecular Animal Breeding, Gene Center, LMU Munich, Feodor-Lynen-StraBe 25, 81377 Munchen, Germany.Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : N-ethyl-N-nitrosourea mutagenesis, immunodeficiency, Zap70, IgE, rodents
Abbreviations used : B6, C3H, ENU, LAT, NK, PLC, OVA, TCR, WT, Zap70
Plan
| Supported by grants from the German Federal Ministry of Science and Education (BMBF 01 KW 9924/8 to T.J. and H.B.) and from the German National Genome Project (UW-S15T03 to T.J., J.R., H.B., and M.O.). |
|
| Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 121 - N° 1
P. 179 - janvier 2008 Retour au numéro
Article précédent
- Correction
- Affinity of IgE and IgG against cross-reactive carbohydrate determinants on plant and insect glycoproteins
- Chunsheng Jin, Brigitte Hantusch, Wolfgang Hemmer, Johannes Stadlmann, Friedrich Altmann
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?