Browsing by Author "Rapaport, F."

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    Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
    (Rockefeller University Press, 2021-06-17) 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.; Guérin, 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.; Özçelik, Tayfun; Picard, C.
    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.
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    Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
    (American Association for the Advancement of Science, 2020) Zhang, Q.; Liu, Z.; Moncada-Velez, M.; Chen, J.; Ogishi, M.; Bigio, B.; Yang, R.; Arias, A. A.; Zhou, Q.; Han, J. E.; Özçelik, Tayfun; Uğurbil, A. C.; Zhang, P.; Rapaport, F.; Li, J.; Spaan, A. N.
    Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-levelmechanismsunderlying life-threatening COVID-19 is of the utmost biological and medical importance.