Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

J Exp Med. 2020 May 4;217(5):e20192319. doi: 10.1084/jem.20192319.

Conor Gruber ¹, Marta Martin-Fernandez ¹, Fatima Ailal ² ³, Xueer Qiu ¹, Justin Taft ¹, Jennie Altman ¹, Jérémie Rosain ⁴ ⁵, Sofija Buta ¹, Aziz Bousfiha ² ³, Jean-Laurent Casanova ⁴ ⁵ ⁶ ⁷ ⁸, Jacinta Bustamante ⁴ ⁵ ⁶ ⁹, Dusan Bogunovic ¹ ¹⁰ ¹¹ ¹²

Affiliations

1 Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, NY.
2 Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco.
3 Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, Centre Hospitalier Universitaire Averroes, Casablanca, Morocco.
4 Paris University, Imagine Institute, Paris, France.
5 Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.
6 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
7 Howard Hughes Medical Institute, New York, NY.
8 Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France.
9 Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France.
10 Department of Pediatrics, Icahn School of Medicine at Mt. Sinai, New York, NY.
11 Precision Immunology Institute, Icahn School of Medicine at Mt. Sinai, New York, NY.
12 Mindich Child Health and Development Institute, Icahn School of Medicine at Mt. Sinai, New York, NY.

PMID: 32092142 DOI: 10.1084/jem.20192319

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.