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

Immunity. 2020 Sep 15;53(3):672-684.e11. doi: 10.1016/j.immuni.2020.07.006.

Conor N Gruber ¹, Jorg J A Calis ², Sofija Buta ¹, Gilad Evrony ³, Jerome C Martin ⁴, Skyler A Uhl ¹, Rachel Caron ¹, Lauren Jarchin ⁵, David Dunkin ⁶, Robert Phelps ⁷, Bryn D Webb ⁸, Jeffrey M Saland ⁹, Miriam Merad ¹⁰, Jordan S Orange ¹¹, Emily M Mace ¹¹, Brad R Rosenberg ¹, Bruce D Gelb ⁸, Dusan Bogunovic ¹²

Affiliations

1 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2 Program in Immunogenomics, The Rockefeller University, New York, NY 10065, USA; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Center for Translational Immunology, Department of Pediatric Immunology & Rheumatology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
3 Center for Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA.
4 Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Université de Nantes, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France; CHU Nantes, Laboratoire d'Immunologie, Center for Immuno Monitoring Nantes-Atlantique (CIMNA), 44000 Nantes, France.
5 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
10 Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
11 Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
12 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].

PMID: 32750333 DOI: 10.1016/j.immuni.2020.07.006

Abstract

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.

Keywords

JAK inhibitors; JAK-STAT signaling; JAK1; cytokine signaling; inborn errors of immunity; monoallelic expression; mosaicis; precision medicine.

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