1. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
- Author
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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, and Boisson, Bertrand
- Subjects
Rare Diseases ,Genetics ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Alleles ,Alternative Splicing ,Child ,Child ,Preschool ,Codon ,Nonsense ,Evolution ,Molecular ,Family ,Female ,Frameshift Mutation ,Genes ,Dominant ,Genetics ,Population ,HEK293 Cells ,Humans ,Infant ,Infant ,Newborn ,Job Syndrome ,Male ,Middle Aged ,Mutation ,Pedigree ,Protein Biosynthesis ,RNA ,Messenger ,STAT3 Transcription Factor ,Medical and Health Sciences ,Immunology - 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.
- Published
- 2021