International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 89 - FROM PHENOTYPE TO GENOTYPE: CHROMOSOMAL MAPPING AND SEQUENCING OF CANDIDATE GENES OF A HYPER IGE MOUSE MUTANT GENERATED BY GENOME WIDE MUTAGENESIS REVEALS A NOVEL MUTATION IN ZAP70

Flaswinkel H
Institute of Molecular Animal Breeding, Gene Center, Feodor-Lynen-Str. 25 82377 München, Germany

Co-Authors: 2) Soewarto D, 3) Köllisch G, 1) Howaldt M, 2) Hrabe de Angelis M, 4) Balling R, 3) Behrendt H, 3) Ring J, 5) Pfeffer K, 1) Wolf E 3) Jakob T
Institutions: 1) Institute of Molecular Animal Breeding, Gene Center, Feodor-Lynen-Str. 25 82377 München, Germany, 2) Institute of Experimental Genetics, GSF Research Center for Environment and Health, Ingolstädter Landstr. 1, Neuherberg, Germany, 3) Division Environmental Dermatology and Allergology, GSF-TUM, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany, 4) Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, 5) Institute for Med. Microbiology, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf

Laboratory animals carrying genetic mutations are of great value to study the biological function of genes. The NEU-Mouse-Mutagenesis Project aims at a large scale production of mouse mutants using the potent mutagen ethyl-nitrosourea (ENU). Using this approach, we have identified a mouse mutant with increased plasma IgE levels and a drastic reduction of peripheral T-cells. Dramatically reduced numbers of T-cells are also found in the spleen. Thymocyte analysis revealed a near complete block in T-cell devellopment at the transition from CD4/CD8 double positive to CD4 or CD8 single positive cells.

Chromosomal mapping revealed a link to a 2.1 cM region localized on chromosome 1. Sequencing of selected candidate genes revealed a novel point mutation at the kinase domain of zeta chain associated protein kinase 70 kD (ZAP70). ZAP70 is involved in early TCR signalling and in thymocyte development. In humans mutations in the ZAP70 kinase domain have been reported in patients with a novel form of severe combined immuno-deficiency disease (SCID) characterized by the absence of peripheral CD8+ T cells and the presence of non-functional CD4 T cells. In conclusion, we have identified a novel mouse mutant with a combined phenotype of hyper IgE, a late block in T cell differentiation and an almost complete absence of peripheral T cells. Chromosomal mapping and sequencing allowed us to identifiy a point mutation in the kinase domain of ZAP70. Additional functional characterization of ZAP70 signalling may reveal novel genotype/phenotype relationships and may lead to a novel animal model for human SCID.


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