| Title: |
SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency |
| Authors: |
Chan, YH; Lundberg, V; Le Pen, J; Yuan, J; Lee, D; Pinci, F; Volpi, S; Nakajima, K; Bondet, V; Åkesson, S; Khobrekar, NV; Bodansky, A; Du, L; Melander, T; Mariaggi, AA; Seeleuthner, Y; Saleh, TS; Chakravarty, D; Marits, P; Dobbs, K; Vonlanthen, S; Hennings, V; Thörn, K; Rinchai, D; Bizien, L; Chaldebas, M; Sobh, A; Özçelik, T; Keles, S; Alkhater, SA; Prando, C; Meyts, I; Wilson, MR; Rosain, J; Jouanguy, E; Aubart, M; Abel, L; Mogensen, TH; Pan-Hammarström, Q; Gao, D; Duffy, D; Cobat, A; Berg, S; Notarangelo, LD; Harschnitz, O; Rice, CM; Studer, L; Casanova, JL; Ekwall, O; Zhang, SY; Bastard, P; Borghesi, A; Bousfiha, A; Boyarchuk, O; Brodin, P; Bustamante, J; Casari, G; Chevalier, R; Christodoulou, J; Colobran, R; Condino-Neto, A; Aldave Becerra, JC; Arkin, L; Andreakos, E; Thorball, CW; Espinosa, S; Flores, C; Geraldo, A; Halwani, R; Hatipoğlu, N; Melaiki, B; Fellay, J; Gagro, A; Itan, Y; Jeewandara, C; Haerynck, F; Mansouri, D; Naesens, L; Ng, LFP; Okamoto, K; Soler- Palacin, P; Renia, L; Onofre, AP; Resnick, IB; Ranco Restrepo, JLF; Rivière, JG; Scherbina, A; Šedivá, A; Seppänen, MRJ; Su, H; Tangye, SG; Temel, SG; Tayoun, AA; Turvey, S; Furkan Uddin, KM; van de Beek, D; Le Voyer, T; Vinh, DC |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2024 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0022-1007 |
| Relation: |
pii: 276864; https://hdl.handle.net/11343/359456 |
| Availability: |
https://hdl.handle.net/11343/359456 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.83C9EDBA |
| Database: |
BASE |