SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
| Title: | SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency |
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| Authors: | Chan Y.H.; Lundberg V.; Le Pen J.; Yuan J.; Lee D.; Pinci F.; Volpi S.; Nakajima K.; Bondet V.; Åkesson S.; Khobrekar N.V.; Bodansky A.; Du L.; Melander T.; Mariaggi A.A.; Seeleuthner Y.; Saleh T.S.; 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 S.A.; Prando C.; Meyts I.; Wilson M.R.; Rosain J.; Jouanguy E.; Aubart M.; Abel L.; Mogensen T.H.; Pan-Hammarström Q.; Gao D.; Duffy D.; Cobat A.; Berg S.; Notarangelo L.D.; Harschnitz O.; Rice C.M.; Studer L.; Casanova J.L.; Ekwall O.; Zhang S.Y.; 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 J.C.; Arkin L.; Andreakos E.; Thorball C.W.; 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 L.F.P.; Okamoto K.; Soler- Palacin P.; Renia L.; Onofre A.P.; Resnick I.B.; Ranco Restrepo J.L.F.; Rivière J.G.; Scherbina A.; Šedivá A.; Seppänen M.R.J.; Su H.; Tangye S.G.; Temel, Şehime Gülsün; Tayoun A.A.; Turvey S.; Furkan Uddin K.M.; van de Beek D.; Le Voyer T.; Vinh D.C. |
| Contributors: | Tıp Fakültesi; Tıbbi Genetik Ana Bilim Dalı; orcid:0000-0002-9802-0880; TEMEL, ŞEHİME GÜLSÜN; 6507885442 |
| Publisher Information: | Rockefeller University Press |
| Publication Year: | 2025 |
| Collection: | Açık Erişim@BUU (Bursa Uludağ Üniversitesi) |
| Subject Terms: | Immunodeficiency; Interferon Responses in SARS Coronavirus Infections |
| 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 boywho 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 ofWT 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. ; European Commission 101057100 ; Vetenskapsrådet 2022-00781, 2018-02752 ; Fondation pour la Recherche Médicale EQU201903007798 ; European Society for Immunodeficiencies P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, R01AI161444 ; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence ANR-10-LABX-62-IBEID ; Horizon 2020 Framework Programme 824110 ; National Human Genome Research Institute UM1HG006504, U24HG008956 ; National Institute of Allergy and Infectious Diseases AI00122, AI001270, AI001265-04 ; Swedish government - ALFGBG-965795 ; EASI-genomics HORIZON-HLTH-2021-DISEASE-04, 101057100 ; Yale High-Performance Computing Center - S10OD018521 ; National Institutes of Health R21AI160576, R01AI163029, R01AI088364 ; Ministry of Higher Education, Research and Innovation MESRI-COVID-19 ; KU Leuven G0B5120N, C16/18/007 ; National Center for Advancing ... |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | Journal of Experimental Medicine; https://hdl.handle.net/11452/51235; 221 |
| DOI: | 10.1084/jem.20231725 |
| Availability: | https://hdl.handle.net/11452/51235; https://doi.org/10.1084/jem.20231725 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.AB9979E7 |
| Database: | BASE |