title: Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in plasma enzyme activities as novel organ-specific disease models.
abstract: Measurement of plasma enzyme activities is part of routine medical examination protocols and provides valuable parameters for the diagnosis of various organ diseases. In the phenotype-driven Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project, clinical chemical blood analysis was carried out on more than 20,000 G1 and G3 offspring of chemically mutagenized inbred C3H mice to detect dominant and recessive mutations leading to deviations in the plasma enzyme activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, alpha-amylase and creatine kinase. We identified a large number of animals that consistently exhibited altered plasma enzyme activities. Transmission of the phenotypic deviations to the subsequent generations led to the successful establishment of mutant lines for each parameter. Breeding experiments in selected lines detected the linkage of the causative mutations to defined chromosomal regions. Subsequently, identification of the mutated genes was successfully carried out in chosen lines, resulting in a novel alkaline phosphatase liver/bone/kidney (Alpl) alteration in one line and the strong indication for a dystrophin (Dmd) alteration in another line. The mouse mutants with abnormal plasma enzyme activities recovered in the Munich ENU project are novel tools for the systematic dissection of the pathogenesis of organ diseases.
authors.affiliation: Department of Veterinary Sciences and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany. b.aigner@gen.vetmed.uni-muenchen.de
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sedlmeier
authors.forename: Martina
authors.initials: M
authors.lastname: Klempt
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wagner
authors.forename: Dian
authors.initials: D
authors.lastname: Michel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D016189:Dystrophin / Q000235:genetics; D004798:Enzymes / Q000097:blood* / Q000235:genetics; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology*; D010641:Phenotype; D000516:alpha-Amylases / Q000097:blood
chemical_list: D016189:Dystrophin; D004798:Enzymes; D009153:Mutagens; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D000469:Alkaline Phosphatase; D000516:alpha-Amylases; D005038:Ethylnitrosourea