PuSH - Publication Server of Helmholtz Zentrum München: An ENU mutagenesis-derived mouse model with a dominant <em>Jak1 </em>mutation resembling phenotypes of systemic autoimmune disease.

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Sabrautzki, S. ; Janas, E. ; Lorenz-Depiereux, B. ; Calzada-Wack, J. ; Aguilar-Pimentel, J.A. ; Rathkolb, B. ; Adler, T. ; Cohrs, C.M. ; Hans, W. ; Diener, S. ; Fuchs, H. ; Gailus-Durner, V. ; Busch, D.H.* ; Höfler, H.* ; Ollert, M.* ; Strom, T.M. ; Wolf, E.* ; Neff, F. ; Hrabě de Angelis, M.

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

Am. J. Pathol. 183, 352-368 (2013)

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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.

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