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

被引：85

作者：

Gruber, Conor ^{[1
]}

Martin-Fernandez, Marta ^{[1
]}

Ailal, Fatima ^{[2
,3
]}

Qiu, Xueer ^{[1
]}

Taft, Justin ^{[1
]}

Altman, Jennie ^{[1
]}

Rosain, Jeremie ^{[4
,5
]}

Buta, Sofija ^{[1
]}

Bousfiha, Aziz ^{[2
,3
]}

Casanova, Jean-Laurent ^{[4
,5
,6
,7
,8
]}

Bustamante, Jacinta ^{[4
,5
,6
,9
]}

Bogunovic, Dusan ^{[1
,10
,11
,12
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[2] King Hassan II Univ, Fac Med & Pharm Casablanca, Lab Clin Immunol Inflammat & Allergy, Casablanca, Morocco

[3] Ctr Hosp Univ Averroes, Childrens Hosp, Dept Pediat Infect Dis, Clin Immunol Unit, Casablanca, Morocco

[4] Paris Univ, Imagine Inst, Paris, France

[5] Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Lab Human Genet Infect Dis, Paris, France

[6] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA

[7] Howard Hughes Med Inst, New York, NY USA

[8] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, Paris, France

[9] Necker Hosp Sick Children, AP HP, Ctr Study Primary Immunodeficiencies, Paris, France

[10] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Precis Immunol Inst, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2020年 / 217卷 / 05期

基金：

美国国家卫生研究院;

关键词：

DEFICIENCY; ALPHA/BETA;

D O I：

10.1084/jem.20192319

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页数：11

共 29 条

[1] JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency [J].

Alsohime, Fahad ;

Martin-Fernandez, Marta ;

Temsah, Mohamad-Hani ;

Alabdulhafid, Majed ;

Le Voyer, Tom ;

Alghamdi, Malak ;

Qiu, Xueer ;

Alotaibi, Najla ;

Alkahtani, Areej ;

Buta, Sofija ;

Jouanguy, Emmanuelle ;

Al-Eyadhy, Ayman ;

Gruber, Conor ;

Hasan, Gamal M. ;

Bashiri, Fahad A. ;

Halwani, Rabih ;

Hassan, Hamdy H. ;

Al-Muhsen, Saleh ;

Alkhamis, Nouf ;

Alsum, Zobaida ;

Casanova, Jean-Laurent ;

Bustamante, Jacinta ;

Bogunovic, Dusan ;

Alangari, Abdullah A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 382 (03) :256-265

[2] STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling [J].

Arimoto, Kei-ichiro ;

Loechte, Sara ;

Stoner, Samuel A. ;

Burkart, Christoph ;

Zhang, Yue ;

Miyauchi, Sayuri ;

Wilmes, Stephan ;

Fan, Jun-Bao ;

Heinisch, Juergen J. ;

Li, Zhi ;

Yan, Ming ;

Pellegrini, Sandra ;

Colland, Frederic ;

Piehler, Jacob ;

Zhang, Dong-Er .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2017, 24 (03) :279-+

[3] Interferons at age 50: past, current and future impact on biomedicine [J].

Borden, Ernest C. ;

Sen, Ganes C. ;

Uze, Gilles ;

Silverman, Robert H. ;

Ransohoff, Richard M. ;

Foster, Graham R. ;

Stark, George R. .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (12) :975-990

[4] Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism [J].

Cavaco, Branca M. ;

Canaff, Lucie ;

Nolin-Lapalme, Alexis ;

Vieira, Margarida ;

Silva, Tiago N. ;

Saramago, Ana ;

Domingues, Rita ;

Rutter, Meilan M. ;

Hudon, Jonathan ;

Gleason, James L. ;

Leite, Valeriano ;

Hendy, Geoffrey N. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2018, 103 (08) :2879-2888

[5] Type I interferonopathies: a novel set of inborn errors of immunity [J].

Crow, Yanick J. .

YEAR IN HUMAN AND MEDICAL GENETICS: INBORN ERRORS OF IMMUNITY I, 2011, 1238 :91-98

[6] JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome [J].

Del Bel, Kate L. ;

Ragotte, Robert J. ;

Saferali, Aabida ;

Lee, Susan ;

Vercauteren, Suzanne M. ;

Mostafavi, Sara A. ;

Schreiber, Richard A. ;

Prendiville, Julie S. ;

Phang, Min S. ;

Halparin, Jessica ;

Au, Nicholas ;

Dean, John M. ;

Priatel, John J. ;

Jewels, Emily ;

Junker, Anne K. ;

Rogers, Paul C. ;

Seear, Michael ;

McKinnon, Margaret L. ;

Turvey, Stuart E. .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2017, 139 (06) :2016-+

[7] Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis [J].

Drutman, Scott B. ;

Haerynck, Filomeen ;

Zhong, Franklin L. ;

Hum, David ;

Hernandez, Nicholas J. ;

Belkaya, Serkan ;

Rapaport, Franck ;

de Jong, Sarah Jill ;

Creytens, David ;

Tavernier, Simon J. ;

Bonte, Katrien ;

De Schepper, Sofie ;

ten Bosch, Jutte van der Werff ;

Lorenzo-Diaz, Lazaro ;

Wullaert, Andy ;

Bossuyt, Xavier ;

Orth, Gerard ;

Bonagura, Vincent R. ;

Beziat, Vivien ;

Abel, Laurent ;

Jouanguy, Emmanuelle ;

Reversade, Bruno ;

Laurent-Casanova, Jean .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (38) :19055-19063

[8] Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 [J].

Duncan, Christopher J. A. ;

Thompson, Benjamin J. ;

Chen, Rui ;

Rice, Gillian, I ;

Gothe, Florian ;

Young, Dan F. ;

Lovell, Simon C. ;

Shuttleworth, Victoria G. ;

Brocklebank, Vicky ;

Corner, Bronte ;

Skelton, Andrew J. ;

Bondet, Vincent ;

Coxhead, Jonathan ;

Duffy, Darragh ;

Fourrage, Cecile ;

Livingston, John H. ;

Pavaine, Julija ;

Cheesman, Edmund ;

Bitetti, Stephania ;

Grainger, Angela ;

Acres, Meghan ;

Innes, Barbara A. ;

Mikulasova, Aneta ;

Sun, Ruyue ;

Hussain, Rafiqul ;

Wright, Ronnie ;

Wynn, Robert ;

Zarhrate, Mohammed ;

Zeef, Leo A. H. ;

Wood, Katrina ;

Hughes, Stephen M. ;

Harris, Claire L. ;

Engelhardt, Karin R. ;

Crow, Yanick J. ;

Randall, Richard E. ;

Kavanagh, David ;

Hambleton, Sophie ;

Briggs, Tracy A. .

SCIENCE IMMUNOLOGY, 2019, 4 (42)

[9] Human IFNAR2 deficiency: Lessons for antiviral immunity [J].

Duncan, Christopher J. A. ;

Mohamad, Siti M. B. ;

Young, Dan F. ;

Skelton, Andrew J. ;

Leahy, T. Ronan ;

Munday, Diane C. ;

Butler, Karina M. ;

Morfopoulou, Sofia ;

Brown, Julianne R. ;

Hubank, Mike ;

Connell, Jeff ;

Gavin, Patrick J. ;

McMahon, Cathy ;

Dempsey, Eugene ;

Lynch, Niamh E. ;

Jacques, Thomas S. ;

Valappil, Manoj ;

Cant, Andrew J. ;

Breuer, Judith ;

Engelhardt, Karin R. ;

Randall, Richard E. ;

Hambleton, Sophie .

SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (307)

[10] Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency [J].

Dupuis, S ;

Jouanguy, E ;

Al-Hajjar, S ;

Fieschi, C ;

Al-Mohsen, IZ ;

Al-Jumaah, S ;

Yang, K ;

Chapgier, A ;

Eidenschenk, C ;

Eid, P ;

Al Ghonaium, A ;

Tufenkeji, H ;

Frayha, H ;

Al-Gazlan, S ;

Al-Rayes, HA ;

Schreiber, RD ;

Gresser, I ;

Casanova, JL .

NATURE GENETICS, 2003, 33 (03) :388-391

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