Article
Author: Prando, Carolina ; Rosain, Jérémie ; Brodin, Petter ; Naesens, Leslie ; Scherbina, Anna ; Borghesi, Alessandro ; Cobat, Aurélie ; Temel, Sehime G. ; Chakravarty, Debanjana ; Seeleuthner, Yoann ; Abel, Laurent ; Rivière, Jacques G. ; Christodoulou, John ; Volpi, Stefano ; Özçelik, Tayfun ; Renia, Laurent ; Bizien, Lucy ; Pinci, Francesca ; Onofre, Aurora Pujol ; Åkesson, Sanna ; Lundberg, Vanja ; Vonlanthen, Sofie ; Vinh, Donald C. ; Haerynck, Filomeen ; Pan-Hammarström, Qiang ; Meyts, Isabelle ; Ekwall, Olov ; Gagro, Alenka ; Aubart, Mélodie ; Berg, Stefan ; Seppänen, Mikko R.J. ; Marits, Per ; Halwani, Rabih ; Melander, Tina ; Duffy, Darragh ; Casanova, Jean-Laurent ; Bondet, Vincent ; Thörn, Karolina ; Uddin, K.M. Furkan ; Resnick, Igor B. ; Notarangelo, Luigi D. ; Boyarchuk, Oksana ; Chan, Yi-Hao ; Mariaggi, Alice-Andrée ; Andreakos, Evangelos ; Tangye, Stuart G ; Fellay, Jacques ; Wilson, Michael R. ; Le Voyer, Tom ; Saleh, Tariq Shikh ; Chevalier, Rémi ; Geraldo, Amyrath ; Šedivá, Anna ; Thorball, Christian W. ; Mogensen, Trine H. ; Khobrekar, Noopur V. ; Melaiki, Brahim ; Sobh, Ali ; Harschnitz, Oliver ; Aldave Becerra, Juan Carlos ; Rinchai, Darawan ; Su, Helen ; Lee, Danyel ; Gao, Daxing ; Itan, Yuval ; Yuan, Jiayi ; Studer, Lorenz ; Condino-Neto, Antonio ; Espinosa, Sara ; Okamoto, Keisuke ; AlKhater, Suzan A. ; Bustamante, Jacinta ; Arkin, Lisa ; Rice, Charles M. ; Hennings, Viktoria ; Ng, Lisa F.P. ; Dobbs, Kerry ; van de Beek, Diederik ; Hatipoğlu, Nevin ; Le Pen, Jérémie ; Casari, Giorgio ; Du, Likun ; Colobran, Roger ; Bastard, Paul ; Nakajima, Koji ; Jouanguy, Emmanuelle ; Turvey, Stuart ; Bodansky, Aaron ; Bousfiha, Aziz ; Franco Restrepo, José Luis ; Mansouri, Davood ; Keles, Sevgi ; Jeewandara, Chandima ; Soler-Palacin, Pere ; Chaldebas, Matthieu ; Tayoun, Ahmad Abou ; Flores, Carlos ; Zhang, Shen-Ying
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.
