An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease

Sibylle Sabrautzki, Eva Janas, Bettina Lorenz-Depiereux, Julia Calzada-Wack, Juan A. Aguilar-Pimentel, Birgit Rathkolb, Thure Adler, Christian Cohrs, Wolfgang Hans, Susanne Diener, Helmut Fuchs, Valerie Gailus-Durner, Dirk H. Busch, Heinz Höfler, Markus Ollert, Tim M. Strom, Eckhard Wolf, Frauke Neff*, Martin Hrabě De Angelis

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)


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 Jak1S645P+/- 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 Jak1S645P 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. Jak1S645P+/- 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, Jak1S645P+/- 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.

Original languageEnglish
Pages (from-to)352-368
Number of pages17
JournalAmerican Journal of Pathology
Issue number2
Publication statusPublished - Aug 2013
Externally publishedYes


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