Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
| Autor: | Capucine Picard, Joëlle Khourieh, Jane Peake, Antoine Guérin, Bertrand Boisson, Aziz Bousfiha, Jamila El Baghdadi, David Hum, Takaki Asano, Jean-Laurent Casanova, Andrew Williams, Simon J. Pelham, Stéphanie Boisson-Dupuis, Peng Zhang, Maya Chrabieh, Luke Droney, Wei-Te Lei, Ilham Fadil, Ji Eun Han, András N Spaan, Qian Zhang, Nevin Hatipoğlu, Franck Rapaport, Anne Puel, Tanwir Habib, Nico Marr, Fatih Celmeli, Vivien Béziat, Joseph Mackie, Biman Saikia, Stuart G. Tangye, Laurent Abel, Tayfun Ozcelik, Juan Li, Sudhir Gupta, Luckshman Ganeshanandan |
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| Přispěvatelé: | Özçelik, Tayfun |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Infectious disease and host defense Dominant negative Innate immunity and inflammation 0302 clinical medicine Immunology and Allergy 10. No inequality STAT3 Child Frameshift Mutation Dominance (genetics) Genes Dominant Translation reinitiation Genetics 0303 health sciences education.field_of_study Middle Aged 3. Good health Pedigree Codon Nonsense 030220 oncology & carcinogenesis Child Preschool Autosomal dominant hyper-IgE syndrome Female Haploinsufficiency Job Syndrome Gene isoform Adult STAT3 Transcription Factor Adolescent Immunology Population Innate Immunity and Inflammation Biology Article Infectious Disease and Host Defense Evolution Molecular 03 medical and health sciences Immunodeficiency Humans Family RNA Messenger education Alleles 030304 developmental biology Human disease genetics Infant Newborn Infant Alternative Splicing Genetics Population HEK293 Cells Protein Biosynthesis Mutation biology.protein Human Disease Genetics |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) are heterozygous for rare STAT3 variants. The mechanism of dominance was recently questioned. The authors show that both in-frame and out-of-frame STAT3 variants underlie AD-HIES by negative dominance and not haploinsufficiency. 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. Graphical Abstract |
| Databáze: | OpenAIRE |
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