Open AccessHuman STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
Author(s) -
Takaki Asano,
Joëlle Khourieh,
Peng Zhang,
Franck Rapaport,
András N. Spaan,
Juan Li,
WeiTe Lei,
Simon J. Pelham,
David Hum,
Maya Chrabieh,
Ji Eun Han,
Antoine Guérin,
Joseph Mackie,
Sudhir Gupta,
Biman Saikia,
Jamila El Baghdadi,
Ilham Fadil,
Aziz Bousfiha,
Tanwir Habib,
Nico Marr,
Luckshman Ganeshanandan,
Jane Peake,
Luke Droney,
Andrew Williams,
Fatih Çelmeli,
Nevin Hatipoğlu,
Tayfun Özçelık,
Capucine Pïcard,
Laurent Abel,
Stuart G. Tangye,
Stéphanie BoissonDupuis,
Qian Zhang,
Anne Puel,
Vivien Béziat,
JeanLaurent Casanova,
Bertrand Boisson
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20202592
Subject(s) - haploinsufficiency , genetics , biology , exon , dominance (genetics) , population , gene , phenotype , medicine , environmental health
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.