Browsing by Author "Asano, T."

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Open Access
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.
Open Access
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
(American Association for the Advancement of Science (AAAS), 2021-08-20) Asano, T.; Boisson, B.; Onodi, F.; Matuozzo, D.; Moncada-Velez, M.; Renkilaraj, M. R. L. M.; Zhang, P.; Meertens, L.; Bolze, A.; Materna, M.; Korniotis, S.; Gervais, A.; Talouarn, E.; Bigio, B.; Seeleuthner, Y.; Bilguvar, K.; Zhang, Y.; Neehus, AL.; Ogishi, M.; Pelham, SJ.; Le Voyer, T.; Rosain, J.; Philippot, Q.; Soler-Palacin, P.; Colobran, R.; Martin-Nalda, A.; Riviere, J. G.; Tandjaoui-Lambiotte, Y.; Chaibi, K.; Shahrooei, M.; Darazam, I. A.; Olyaei, NA.; Mansouri, D.; Palabiyik, F.; Özçelik, Tayfun; Novelli, G.; Novelli, A.; Casari, G.; Aiuti, A.; Carrera, P.; Bondesan, S.; Barzaghi, F.; Rovere-Querini, P.; Tresoldi, C.; Franco, J. L.; Rojas, J.; Reyes, LF.; Bustos, IG.; Arias, AA.; Morelle, G.; Kyheng, C.; Troya, J.; Planas-Serra, L.; Schluter, A.; Gut, M.; Pujol, A.; Allende, L. M.; Rodriguez-Gallego, C.; Flores, C.; Cabrera-Marante, O.; Pleguezuelo, DE.; de Diego, R. P.; Keles, S.; Aytekin, G.; Akcan, O. M.; Bryceson, Y. T.; Bergman, P.; Brodin, P.; Smole, D.; Smith, C. I. E.; Norlin, A. C.; Campbell, T. M.; Covill, LE.; Hammarstrom, L.; Pan-Hammarstrom, Q.; Abolhassani, H.; Mane, S.; Marr, N.; Ata, M.; Al Ali, F.; Khan, T.; Spaan, A. N.; Dalgard, C. L.; Bonfanti, P.; Biondi, A.; Tubiana, S.; Burdet, C.; Nussbaum, R.; Kahn-Kirby, A.; Snow, AL.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Zhang, S. Y.; Beziat, V.; Lifton, R. P.; Bastard, P.; Notarangelo, L. D.; Abel, L.; Su, H. C.; Jouanguy, E.; Amara, A.; Soumelis, V.; Cobat, A.; Zhang, Q.; Casanova, J. L.
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10−5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10−4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.