{Reference Type}: Journal Article
{Title}: SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
{Author}: 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;
{Journal}: J Exp Med
{Volume}: 221
{Issue}: 9
{Year}: 2024 09 2
{Factor}: 17.579
{DOI}: 10.1084/jem.20231725
{Abstract}: 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.