Yi-Hao ChanLundberg, VanjaPen, Jérémie LeYuan, JiayiLee, DanyelPinci, FrancescaVolpi, StefanoNakajima, KojiBondet, VincentLinnéa Åkesson, Sanna EmmyKhobrekar, NoopurBodansky, AaronDu, LikunMelander, TinaMariaggi, Alice-AndréeSeeleuthner, YoannSaleh, Tariq ShikhChakravarty, DebanjanaMarits, PerDobbs, KerryVonlanthen, SofieHennings, ViktoriaThörn, KarolinaRinchai, DarawanBizien, LucyChaldebas, MatthieuSobh, AliÖzçelik, TayfunKeles, SevgiAlKhater, SuzanPrando, CarolinaMeyts, IsabelleWilson, MichaelRosain, JeremieJouanguy, EmmanuelleAubart, MelodieAbel, LaurentMogensen, Trine HyrupPan-Hammarström, QiangGao, DaxingDuffy, DarraghCobat, AurélieBerg, StefanNotarangelo, LuigiHarschnitz, OliverRice, Charles M.Studer, LorenzCasanova, Jean-LaurentEkwall, OlovZhang, Shen-Ying2025-02-262025-02-262024-07-180022-1007https://hdl.handle.net/11693/116850Inherited 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.EnglishCC BY 4.0 DEED (Attribution 4.0 International)https://creativecommons.org/licenses/by/4.0/ImmunodeficiencyArticle10.1084/jem.202317251540-9538