Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

被引：29

作者：

Asano, Takaki ^{[1
]}

Khourieh, Joelle ^{[2
,3
]}

Zhang, Peng ^{[1
]}

Rapaport, Franck ^{[1
]}

Spaan, Andras N. ^{[1
]}

Li, Juan ^{[1
]}

Lei, Wei-Te ^{[1
]}

Pelham, Simon J. ^{[1
]}

Hum, David ^{[1
]}

Chrabieh, Maya ^{[2
,3
]}

Han, Ji Eun ^{[1
]}

Guerin, Antoine ^{[4
,5
]}

Mackie, Joseph ^{[4
,5
]}

Gupta, Sudhir ^{[6
]}

Saikia, Biman ^{[7
]}

Baghdadi, Jamila E., I ^{[8
]}

Fadil, Ilham ^{[9
,10
]}

Bousfiha, Aziz ^{[9
,10
]}

Habib, Tanwir ^{[11
]}

Marr, Nico ^{[11
,12
]}

Ganeshanandan, Luckshman ^{[13
]}

Peake, Jane ^{[14
]}

Droney, Luke ^{[15
]}

Williams, Andrew ^{[16
]}

Celmeli, Fatih ^{[17
]}

Hatipoglu, Nevin ^{[18
]}

Ozcelik, Tayfun ^{[19
]}

Picard, Capucine ^{[20
,21
,22
,23
]}

Abel, Laurent ^{[1
,2
,3
]}

Tangye, Stuart G. ^{[4
,5
]}

Boisson-Dupuis, Stephanie ^{[1
,2
,3
]}

Zhang, Qian ^{[1
,2
,3
]}

Puel, Anne ^{[1
,2
,3
]}

Beziat, Vivien ^{[1
,2
,3
]}

Casanova, Jean-Laurent ^{[1
,2
,3
,24
]}

Boisson, Bertrand ^{[1
,2
,3
]}

机构：

[1] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

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

[3] Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France

[4] Garvan Inst Med Res, Darlinghurst, NSW, Australia

[5] Univ New South Wales, Fac Med & Hlth, St Vincents Clin Sch, Sydney, NSW, Australia

[6] Univ Calif Irvine, Sch Med, Dept Med, Div Basic & Clin Immunol, Irvine, CA 92717 USA

[7] Post Grad Inst Med Educ & Res, Dept Immunopathol, Chandigarh, India

[8] Mil Hosp Mohamed V, Genet Unit, Rabat, Morocco

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

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

[11] Qatar Fdn, Res Branch, Sidra Med, Doha, Qatar

[12] Hamad Bin Khalifa Univ, Qatar Fdn, Coll Hlth & Life Sci, Doha, Qatar

[13] Fiona Stanley Hosp, Dept Clin Immunol, PathWest Lab Med Western Australia, Perth, WA, Australia

[14] Queensland Childrens Hosp, South Brisbane, Australia

[15] Princess Alexandra Hosp, Dept Clin Immunol, Brisbane, Qld, Australia

[16] Childrens Hosp Westmead, Immunol Lab, Westmead, NSW, Australia

[17] Univ Med Sci Antalya Educ & Res Hosp, Dept Allergy & Immunol, Antalya, Turkey

[18] Bakirkoy Dr Sadi Konuk Educ & Training Hosp, Istanbul, Turkey

[19] Bilkent Univ, Dept Mol Biol & Genet, Ankara, Turkey

[20] Univ Paris, Paris, France

[21] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Study Ctr Primary Immunodeficiencies, Paris, France

[22] Inst Natl Sante & Rech Med UMR 1163, Imagine Inst, Lab Lymphocyte Activat & Susceptibil EBV Infect, Paris, France

[23] Necker Hosp Sick Children, Assistance Publ Hop Paris, Pediat Immunol Hematol Unit, Paris, France

[24] Howard Hughes Med Inst, New York, NY 10032 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2021年 / 218卷 / 08期

基金：

荷兰研究理事会; 美国国家卫生研究院;

关键词：

HYPERIMMUNOGLOBULIN-E SYNDROME; SIGNAL TRANSDUCER; CLINICAL-FEATURES; POINT MUTATIONS; KEY FINDINGS; GENE; DEFICIENCY; DOCK8; ACTIVATOR; PATIENT;

D O I：

10.1084/jem.20202592

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

引用

页数：28

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