SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
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Chan, Yi-Hao | Lundberg, Vanja | Le Pen, Jérémie | Yuan, Jiayi | Lee, Danyel | Pinci, Francesca | Volpi, Stefano | Nakajima, Koji | Bondet, Vincent | Åkesson, Sanna | Khobrekar, Noopur | Bodansky, Aaron | Du, Likun | Melander, Tina | Mariaggi, Alice-Andrée | Seeleuthner, Yoann | Saleh, Tariq Shikh | Chakravarty, Debanjana | Marits, Per | Dobbs, Kerry | Vonlanthen, Sofie | Hennings, Viktoria | Thörn, Karolina | Rinchai, Darawan | Bizien, Lucy | Chaldebas, Matthieu | Sobh, Ali | Özçelik, Tayfun | Keles, Sevgi | Alkhater, Suzan | Prando, Carolina | Meyts, Isabelle | Wilson, Michael | Rosain, Jérémie | Jouanguy, Emmanuelle | Aubart, Mélodie | Abel, Laurent | Mogensen, Trine | Pan-Hammarström, Qiang | Gao, Daxing | Duffy, Darragh | Cobat, Aurélie | Berg, Stefan | Notarangelo, Luigi | Harschnitz, Oliver | Rice, Charles | Studer, Lorenz | Casanova, Jean-Laurent | Ekwall, Olov | Zhang, Shen-Ying | Bastard, Paul | Borghesi, Alessandro | Bousfiha, Aziz | Boyarchuk, Oksana | Brodin, Petter | Bustamante, Jacinta | Casari, Giorgio | Chevalier, Rémi | Christodoulou, John | Colobran, Roger | Condino-Neto, Antonio | Aldave Becerra, Juan Carlos | Arkin, Lisa | Andreakos, Evangelos | Thorball, Christian | Espinosa, Sara | Flores, Carlos | Geraldo, Amyrath | Halwani, Rabih | Hatipoğlu, Nevin | Melaiki, Brahim | Fellay, Jacques | Gagro, Alenka | Itan, Yuval | Jeewandara, Chandima | Haerynck, Filomeen | Mansouri, Davood | Naesens, Leslie | Ng, Lisa F.P. | Okamoto, Keisuke | Soler-Palacin, Pere | Renia, Laurent | Onofre, Aurora Pujol | Resnick, Igor | Franco Restrepo, José Luis | Rivière, Jacques | Scherbina, Anna | Šedivá, Anna | Seppänen, Mikko R.J. | Su, Helen | Tangye, Stuart | Temel, Sehime | Tayoun, Ahmad Abou | Turvey, Stuart | Uddin, K.M. Furkan | van de Beek, Diederik | Le Voyer, Tom | Vinh, Donald | Effort, Covid Human Genetic
Edité par
CCSD ; Rockefeller University Press -
International audience.
Inherited deficiency of the RNA lariat–debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)–derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron–intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
