Hastened by new technologies, the study of monogenic immune disease is beginning to resolve unusual phenotypes, genetic complexities and intricate immunologic mechanisms. Here, we describe a patient with severe, early-onset immunodysregulatory disease marked by membranous nephropathy, eosinophilic enteritis, widespread dermatitis and growth disturbances. Whole-exome sequencing uncovered a de novo mutation (S703I) in JAK1, which mediates signal transduction from a remarkably broad range of cytokines by phosphorylation of STAT proteins.
We utilized genomic, molecular and multi-parametric immunological tools to probe the role of S703I JAK1in vitroand ex vivoin order to investigate clinical dysfunction in vivo.
In vitro, ectopic expression with S703I JAK1 increased basal and cytokine-induced STAT signaling. Surprisingly, S703I could increase signaling independent of its own catalytic activity, indicating that S703I trans-activates partnering JAKs. Next, CyTOF analysis of patient blood revealed upregulated STAT phosphorylation profiles unique to each immune cell. When cytokine-stimulated ex vivo, patient leukocytes exhibited heightened response along some cytokine pathways but not others. Furthering this complexity, patient cells demonstrated non-canonical STAT phosphorylation, suggesting that S703I JAK1 is promiscuous as well as hyperactive. Next, digital droplet PCR and single-cell-RNA-sequencing uncovered genetic mosaicism, monoallelic expression of JAK1, and mutant-cell-enriched interferon signatures. Lastly, JAK inhibitors were evaluated for personalized therapy. After demonstration of efficacy ex vivoand in vitro, tofacitinib was initiated and clinical disease resolved rapidly.
This study of a novel gain-of-function JAK1mutation uncovered novel regulatory and transcriptomic processes governing basic JAK1 function, and reveals the clinical consequences of JAK1 dysfunction.