Within the Munich ENU Mutagenesis Project, MEP (project leader Sibylle Sabrautzki) Helmholtz Zentrum München, scientists from the Institute of Experimental Genetics and German Mouse Clinic and colleagues from the Institute of Human Genetics identified a new dominant point mutation in the Jak1 gene (p.Ser645Pro). The mutation affects the conserved serine of the pseudokinase domain and corresponds to a somatic human mutation (p.Ser646Phe) which induces constitutive activation of the Janus kinase (JAK)/STAT pathway. The JAK-STAT pathway has proved to be essential for many immunological processes playing a critical role in the pathogenesis of autoimmune diseases and cancer. Furthermore the pathway members play important roles in signalling downstream of cytokine receptor activation and are implicated in various physiological processes, including hematopoietic, neuronal and hepatic systems.
The Jak1S645P+/- mouse mutants were analysed in the German Mouse Clinic. All mutant mice depicted a significant increase of total alkaline phosphatase activities and total inorganic calcium values in plasma together with hypophosphatemia indicating an impaired bone turnover. This was confirmed by decreased parameters in pQCT and strongly decreased bone morphometric values in µCT measurements and by a significant increase of carboxy-terminal collagen cross-link-1 (CTX-1) levels in plasma.
Further, the morphological investigation showed a progressive structural deterioration of ears starting at the age of four months with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from seven months of age. The immune histochemical 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.
Taken together, Jak1S645P+/- mice showed an increased activation of the IL-6eJAKeSTAT 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.
Sabrautzki et al., 2013, An ENU Mutagenesis-Derived Mouse Model with a Dominant Jak1 Mutation Resembling Phenotypes of Systemic Autoimmune Disease, The American Journal of Pathology, Vol. 183, No. 2, August 2013. doi:10.1016/j.ajpath.2013.04.027