An ENU Mutagenesis-Derived Mouse Model with a Dominant Jak1 Mutation Resembling Phenotypes of Systemic Autoimmune Disease

作者：Sabrautzki Sibylle; Janas Eva; Lorenz Depiereux Bettina; Calzada Wack Julia; Aguilar Pimentel Juan A; Rathkolb Birgit; Adler Thure; Cohrs Christian; Hans Wolfgang; Diener Susanne; Fuchs Helmut; Gailus Durner Valerie; Busch Dirk H; Hoefler Heinz; Ollert Markus; Strom Tim M; Wolf Eckhard; Neff Frauke^*; de Angelis Martin Hrabe

来源：American Journal Of Pathology, 2013, 183(2): 352-368.

DOI：10.1016/j.ajpath.2013.04.027

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.

• 出版日期2013-8
• 单位河北医科大学