STAT5 variants in the pathogenesis of inflammatory bowel disease

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Inflammatory bowel disease (IBD), with its two main entities Crohn's disease and ulcerative colitis, results from a complex interplay of genetic and environmental factors. Genetic analyses revealed IBD-associated polymorphisms in more than 200 genetic loci. However, the mechanisms which link individual genes and polymorphisms to IBD are still poorly understood. The identification of monogenic forms of IBD in which the loss of individual genes is associated with IBD, has tremendously contributed to our understanding of genetic pathways to IBD. Specifically, this work has revealed vastly different pathways to IBD based on defects in the intestinal epithelium, innate immunity or adaptive immunity. Moreover, these studies have highlighted new avenues to personalized treatment of IBD. The screening for known or novel monogenic forms of IBD has become an important aspect of clinical diagnostics, particularly for pediatric and familial forms of IBD. Through such diagnostics, we could recently identify a missense variant in signal transducer and activator of transcription (STAT) 5A (STAT5A E518K) in a female patient with severe, early-onset Crohn's disease. STAT5A is a transcription factor with important roles in immunity, but variants in STAT5A have so far not been linked to monogenic forms of IBD. Functional investigations demonstrated that STAT5A E518K was associated with reduced STAT5A expression and function. To investigate its function in vivo, we capitalized on conservation of the STAT5A E518 residue and its flanking region in mice and engineered mice carrying this variant in the endogenous Stat5a locus. We could demonstrate that STAT5A E518K is associated with defects in immunity and promotes susceptibility to chemically induced colitis. Based on these preliminary data, we aim to characterize the role of this and other STAT5 variants in the pathogenesis of IBD. Specifically, we will (i) investigate whether STAT5A E518K is associated with alterations in intestinal epithelial function or mucosal immunity in mice and in the patient carrying STAT5A E518K; (ii) study whether mice carrying STAT5A E518K exhibit susceptibility to chemical, immunological, and microbial triggers of intestinal inflammation; and (iii) investigate the roles of other STAT5A and STAT5B variants in the pathogenesis of IBD. Together, this work will characterize STAT5 variants as a potential monogenic origin of IBD and shall identify the pathways that link STAT5 to IBD.