PDF(Pubmed)
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.
摘要：
RNA套索脱支酶1（DBR1）的遗传性缺乏是脑干病毒性脑炎的罕见病因。疾病的细胞基础和病毒易感性的范围尚不清楚。我们报告了一个14岁男孩的遗传性DBR1缺乏症，该男孩患有孤立的SARS-CoV-2脑干脑炎。该患者是先前报道的低形态和致病性DBR1变体(I120T)的纯合子。始终如一，来自此和另一个无关亲属的受影响个体的DBR1I120T/I120T成纤维细胞具有类似的低水平的DBR1蛋白和高水平的RNAlarats。DBR1I120T/I120T人类多能干细胞（hPSC）来源的后脑神经元对SARS-CoV-2感染高度敏感。DBR1I120T/I120T成纤维细胞和后脑神经元中的外源性WTDBR1表达拯救了RNA套索积累表型。此外，外源RNA的表达，模仿DBR1缺乏，WT后脑神经元对SARS-CoV-2感染的易感性增加。DBR1的先天性错误损害后脑神经元固有的抗病毒免疫，易患脑干病毒感染，包括SARS-CoV-2。
