title: Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis.
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 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.
  
  
  CONCLUSIONS
  Random genome-wide mutagenesis combined with a phenotype screen can be used to generate novel mouse mutants with primary cellular immunodeficiencies.
authors.affiliation: Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany. thilo.jakob@uniklinik-freiburg.de
authors.forename: Thilo
authors.initials: T
authors.lastname: Jakob
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Köllisch
authors.forename: Maike
authors.initials: M
authors.lastname: Howaldt
authors.forename: Mayte
authors.initials: M
authors.lastname: Bewersdorff
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Marcel L
authors.initials: ML
authors.lastname: Müller
authors.forename: Nadja
authors.initials: N
authors.lastname: Sandholzer
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.forename: Martin
authors.initials: M
authors.lastname: Mempel
authors.forename: Markus
authors.initials: M
authors.lastname: Ollert
authors.forename: Antonie
authors.initials: A
authors.lastname: Neubauer
authors.forename: Dian A
authors.initials: DA
authors.lastname: Soewarto
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Johannes
authors.initials: J
authors.lastname: Ring
authors.forename: Heidrun
authors.initials: H
authors.lastname: Behrendt
authors.forename: Heinrich
authors.initials: H
authors.lastname: Flaswinkel
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D005038:Ethylnitrosourea; D016678:Genome / Q000235:genetics*; D007073:Immunoglobulin E / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D010641:Phenotype; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D000477:Alkylating Agents; D007073:Immunoglobulin E; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D005038:Ethylnitrosourea