title: An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease.
abstract: Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus-like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development.
authors.affiliation: Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sabrautzki
authors.forename: Eva
authors.initials: E
authors.lastname: Janas
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depiereux
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Juan A
authors.initials: JA
authors.lastname: Aguilar-Pimentel
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.forename: Christian
authors.initials: C
authors.lastname: Cohrs
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Susanne
authors.initials: S
authors.lastname: Diener
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Markus
authors.initials: M
authors.lastname: Ollert
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004427:Ear Diseases / Q000235:genetics; D005260:Female; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D017674:Hypophosphatemia / Q000235:genetics / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D016296:Mutagenesis / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012873:Skin Diseases, Genetic / Q000235:genetics; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053613:Janus Kinase 1