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


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.

SUBMITTER: Asano T 

PROVIDER: S-EPMC8217968 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Asano Takaki T   Khourieh Joëlle J   Zhang Peng P   Rapaport Franck F   Spaan András N AN   Li Juan J   Lei Wei-Te WT   Pelham Simon J SJ   Hum David D   Chrabieh Maya M   Han Ji Eun JE   Guérin Antoine A   Mackie Joseph J   Gupta Sudhir S   Saikia Biman B   Baghdadi Jamila E I JEI   Fadil Ilham I   Bousfiha Aziz A   Habib Tanwir T   Marr Nico N   Ganeshanandan Luckshman L   Peake Jane J   Droney Luke L   Williams Andrew A   Celmeli Fatih F   Hatipoglu Nevin N   Ozcelik Tayfun T   Picard Capucine C   Abel Laurent L   Tangye Stuart G SG   Boisson-Dupuis Stéphanie S   Zhang Qian Q   Puel Anne A   Béziat Vivien V   Casanova Jean-Laurent JL   Boisson Bertrand B  

The Journal of experimental medicine 20210617 8


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 v  ...[more]

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