title: A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model.
abstract: OBJECTIVE
  It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model.
  
  
  METHODS
  In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic.
  
  
  RESULTS
  A novel missense mutation in the phospholipase Cγ2 gene (Plcg2) was identified in Ali14/+ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/+ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell ratio, up-regulation of Ig, alterations in body composition, and a reduction in cholesterol and triglyceride levels in peripheral blood. In addition, spermatozoa from Ali14/+ mice failed to fertilize eggs in vitro, despite the normal fertility of the Ali14/+ male mice in vivo.
  
  
  CONCLUSIONS
  These results suggest that the Plcg2-mediated pathways play a crucial role in various metabolic and sperm functions, in addition to initiating and maintaining the immune system. These findings may indicate the importance of the Ali14/+ mouse strain as a model for systemic inflammatory diseases and inflammation-related metabolic changes in humans.
authors.affiliation: Tokai University School of Medicine, Kanagawa, Japan. abeko@is.icc.u-tokai.ac.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Auke
authors.initials: A
authors.lastname: Boersma
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Philipp
authors.initials: P
authors.lastname: Yu
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Thure
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authors.lastname: Adler
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.forename: Miriam
authors.initials: M
authors.lastname: Maraslioglu
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Kametani
authors.forename: Shin
authors.initials: S
authors.lastname: Shimada
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.forename: Susan
authors.initials: S
authors.lastname: Marschall
authors.forename: Dian
authors.initials: D
authors.lastname: Soewarto
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wagner
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics*; D001823:Body Composition / Q000235:genetics*; D005038:Ethylnitrosourea / Q000494:pharmacology; D005434:Flow Cytometry; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation / Q000187:drug effects; D051966:Phospholipase C gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013081:Sperm Motility / Q000235:genetics
chemical_list: D051966:Phospholipase C gamma; D005038:Ethylnitrosourea