학술논문
Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
Document Type
article
Author
Asano, Takaki; Khourieh, Joëlle; Zhang, Peng; Rapaport, Franck; Spaan, András N; Li, Juan; Lei, Wei-Te; Pelham, Simon J; Hum, David; Chrabieh, Maya; Han, Ji Eun; Guérin, Antoine; Mackie, Joseph; Gupta, Sudhir; Saikia, Biman; Baghdadi, Jamila EI; Fadil, Ilham; Bousfiha, Aziz; Habib, Tanwir; Marr, Nico; Ganeshanandan, Luckshman; Peake, Jane; Droney, Luke; Williams, Andrew; Celmeli, Fatih; Hatipoglu, Nevin; Ozcelik, Tayfun; Picard, Capucine; Abel, Laurent; Tangye, Stuart G; Boisson-Dupuis, Stéphanie; Zhang, Qian; Puel, Anne; Béziat, Vivien; Casanova, Jean-Laurent; Boisson, Bertrand
Source
Journal of Experimental Medicine. 218(8)
Subject
Language
Abstract
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.