Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.
Adolescent
COVID-19
/ mortality
Catalytic Domain
/ genetics
Cell Line
Cytokines
/ metabolism
Female
Gain of Function Mutation
/ genetics
Genotype
HEK293 Cells
Hereditary Autoinflammatory Diseases
/ drug therapy
Humans
Janus Kinase 1
/ antagonists & inhibitors
Mosaicism
Piperidines
/ therapeutic use
Precision Medicine
/ methods
Pyrimidines
/ therapeutic use
Signal Transduction
/ immunology
Systemic Inflammatory Response Syndrome
/ drug therapy
JAK inhibitors
JAK-STAT signaling
JAK1
cytokine signaling
inborn errors of immunity
monoallelic expression
mosaicis
precision medicine
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
23
04
2020
revised:
02
07
2020
accepted:
08
07
2020
pubmed:
5
8
2020
medline:
23
4
2021
entrez:
5
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32750333
pii: S1074-7613(20)30313-7
doi: 10.1016/j.immuni.2020.07.006
pmc: PMC7398039
pii:
doi:
Substances chimiques
Cytokines
0
Piperidines
0
Pyrimidines
0
tofacitinib
87LA6FU830
JAK1 protein, human
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
672-684.e11Subventions
Organisme : NIAID NIH HHS
ID : R01 AI127372
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI120989
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI129827
Pays : United States
Organisme : NIH HHS
ID : DP5 OD012142
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI137275
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK117218
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD075735
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI134366
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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