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


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.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Asano, T.; Khourieh, J.; Zhang, P.; Rapaport, F.; Spaan, A. N.; Li, J.; Lei, W. T.; Pelham, S. J.; Hum, D.; Chrabieh, M.; Han, J. E.; Guerin, A.; Mackie, J.; Gupta, S.; Saikia, B.; Baghdadi, J. E. I.; Fadil, I.; Bousfiha, A.; Habib, T.; Marr, N.; Ganeshanandan, L.; Peake, J.; Droney, L.; Williams, A.; Celmeli, F.; Hatipoglu, N.; Ozcelik, T.; Picard, C.; Abel, L.; Tangye, S. G.; Boisson-Dupuis, S.; Zhang, Q.; Puel, A.; Beziat, V.; Casanova, J. L.; Boisson, B.
Responsible Garvan Author Antoine Guerin
Published Date 2021-08-31
Published Volume 218
Published Issue 8
Published Pages e20202592
Status Published in-print
DOI 10.1084/jem.20202592
URL link to publisher's version