PUBLICATION

Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation

Authors
Biggs, C.M., Cordeiro-Santanach, A., Prykhozhij, S.V., Deveau, A.P., Lin, Y., Del Bel, K.L., Orben, F., Ragotte, R.J., Saferali, A., Mostafavi, S., Dinh, L., Dai, D., Weinacht, K.G., Dobbs, K., Ott de Bruin, L., Sharma, M., Tsai, K., Priatel, J.J., Schreiber, R.A., Rozmus, J., Hosking, M.C., Shopsowitz, K.E., McKinnon, M.L., Vercauteren, S., Seear, M., Notarangelo, L.D., Lynn, F.C., Berman, J.N., Turvey, S.E.
ID
ZDB-PUB-221223-4
Date
2022
Source
JCI insight   7(24): (Journal)
Registered Authors
Berman, Jason
Keywords
Allergy, Bone marrow differentiation, Hematology, Immunology
MeSH Terms
  • Animals
  • Hypersensitivity*/genetics
  • Humans
  • Hypersensitivity, Immediate*
  • Eosinophilia*/genetics
  • Inflammation/genetics
  • Zebrafish
  • Induced Pluripotent Stem Cells*
  • Janus Kinase 1/genetics
  • Child
  • Gain of Function Mutation
(all 11)
PubMed
36546480 Full text @ JCI Insight
Abstract
Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
mitfaw2/w2; mpv17a9/a9; hsi13Tg/+standard conditionsPrim-15
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsPrim-5
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsPrim-15
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsPrim-15
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsLong-pec
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsLong-pec
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsLong-pec
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+standard conditionsLong-pec
mitfaw2/w2; mpv17a9/a9; hsi14Tg/+chemical treatment by environment: ruxolitinibPrim-15
1 - 9 of 9
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    hsi13TgTransgenic Insertion
      hsi14TgTransgenic Insertion
        w2
          		Point Mutation
          1 - 4 of 4
          Show
          Human Disease / Model
          Human Disease Fish Conditions Evidence
          allergic diseaseTAS
          1 - 1 of 1
          Show
          Sequence Targeting Reagents
          No data available
          Fish
          Fish
          mitfaw2/w2; mpv17a9/a9; hsi13Tg/+
          mitfaw2/w2; mpv17a9/a9; hsi14Tg/+
          1 - 2 of 2
          Show
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          ECFPEFGECFP
          sfGFPEFGsfGFP
          1 - 2 of 2
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          Mapping
          No data available
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          Citation
          Biggs, C.M., Cordeiro-Santanach, A., Prykhozhij, S.V., Deveau, A.P., Lin, Y., Del Bel, K.L., Orben, F., Ragotte, R.J., Saferali, A., Mostafavi, S., Dinh, L., Dai, D., Weinacht, K.G., Dobbs, K., Ott de Bruin, L., Sharma, M., Tsai, K., Priatel, J.J., Schreiber, R.A., Rozmus, J., Hosking, M.C., Shopsowitz, K.E., McKinnon, M.L., Vercauteren, S., Seear, M., Notarangelo, L.D., Lynn, F.C., Berman, J.N., Turvey, S.E. (2022) Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation. JCI insight. 7(24):.