Mouse Model of STAT3 Mutation Resulting in Job's Syndrome Diverges from Human Pathology.

Abstract

mutations are commonly observed in human pathology yet have no uniform patient presentation. Their effects range from cancer and autoimmunity to primary immunodeficiencies and bone deformity. Designing animal models of those mutations can help researchers identify their direct effects to better inform the clinical setting. In this manuscript, we report a mouse model harboring the same mutation as an autosomal-dominant hyper-IgE syndrome (AD-HIES) patient reported in the literature. Surprisingly, while the deletion of five amino acids in the SH2 domain of STAT3 did result in frequency changes in several immune populations as measured by complete blood count and flow cytometry analysis, it did not yield the expected phenotype of AD-HIES, with no increase in serum IgE or eosinophil count. We additionally provide structural analysis of thedeletion, visualizing changes in protein architecture and potential effects on the neighboring Y705 phosphorylation site. Our model showcases the sexually dimorphic immune dysregulation caused by amutation and highlights that predicted gain- and loss-of-function mutations can yield unexpected phenotypes.