Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy.
J Exp Med
; 217(5)2020 05 04.
Article
en En
| MEDLINE
| ID: mdl-32092142
ABSTRACT
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Interferón Tipo I
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Ubiquitina Tiolesterasa
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Factor de Transcripción STAT2
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Mutación con Ganancia de Función
Idioma:
En
Revista:
J Exp Med
Año:
2020
Tipo del documento:
Article