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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Nodular Regenerative Hyperplasia ; Acute Lymphoblastic-leukemia ; Signal-transduction Pathway ; Lupus-erythematosus ; B-cells ; Tyrosine Kinase ; I Interferon ; Genome-wide ; Mice ; Liver
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0002-9440
e-ISSN 1525-2191
Journal American Journal of Pathology, The
Quellenangaben Volume: 183, Issue: 2, Pages: 352-368 Article Number: , Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Pathology (PATH)
Institute of Human Genetics (IHG)
POF-Topic(s) 30201 - Metabolic Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-500600-003
G-500300-001
G-500600-001
G-500700-001
G-501900-063
PubMed ID 23791841
DOI 10.1016/j.ajpath.2013.04.027
WOS ID WOS:000322611700005
Scopus ID 84880625779
Erfassungsdatum 2013-07-22
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