Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles. [Display omitted] •Janus kinase (JAK1) mutation underlies monogenic autoinflammatory disease•S703I mutation enhances downstream signaling by transactivation of partnering JAKs•Mosaicism and monoallelic expression shape JAK1 transcription patterns•JAK inhibitor therapy resolves clinical disease Monogenic errors of the Janus kinase (JAK) family, essential signal transduction hubs of the immune system, have dire consequences in immune function. Gruber et al. describe a JAK1 gain-of-function mutation with mosaicism and monoallelic expression that underlies a multi-system autoinflammatory disease, which is rescued by JAK inhibitor therapy.