Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy.
Amino Acid Sequence
Base Sequence
Cell Line
Female
Gain of Function Mutation
/ genetics
Gene Expression Regulation
Homozygote
Humans
Infant, Newborn
Interferon Type I
/ metabolism
Male
Pedigree
Phenotype
Protein Domains
STAT2 Transcription Factor
/ chemistry
Ubiquitin Thiolesterase
/ deficiency
Exome Sequencing
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
04 05 2020
04 05 2020
Historique:
received:
10
12
2019
revised:
13
01
2020
accepted:
07
02
2020
entrez:
25
2
2020
pubmed:
25
2
2020
medline:
29
12
2020
Statut:
ppublish
Résumé
Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I-stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.
Identifiants
pubmed: 32092142
pii: 133837
doi: 10.1084/jem.20192319
pmc: PMC7201920
pii:
doi:
Substances chimiques
Interferon Type I
0
STAT2 Transcription Factor
0
STAT2 protein, human
0
USP18 protein, human
EC 3.4.19.12
Ubiquitin Thiolesterase
EC 3.4.19.12
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
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI127372
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000043
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI129827
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG008051
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI089970
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD075735
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI134366
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI138363
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI095983
Pays : United States
Informations de copyright
© 2020 Gruber et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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