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Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.
Cell ( IF 45.5 ) Pub Date : 2018-Feb-22 , DOI: 10.1016/j.cell.2018.02.019
Shen-Ying Zhang 1 , Nathaniel E Clark 2 , Catherine A Freije 3 , Elodie Pauwels 4 , Allison J Taggart 5 , Satoshi Okada 6 , Hanna Mandel 7 , Paula Garcia 8 , Michael J Ciancanelli 4 , Anat Biran 4 , Fabien G Lafaille 4 , Miyuki Tsumura 6 , Aurélie Cobat 9 , Jingchuan Luo 10 , Stefano Volpi 11 , Bastian Zimmer 12 , Sonoko Sakata 6 , Alexandra Dinis 13 , Osamu Ohara 14 , Eduardo J Garcia Reino 4 , Kerry Dobbs 15 , Mary Hasek 4 , Stephen P Holloway 2 , Karen McCammon 2 , Stacy A Hussong 16 , Nicholas DeRosa 17 , Candice E Van Skike 17 , Adam Katolik 18 , Lazaro Lorenzo 9 , Maki Hyodo 19 , Emilia Faria 20 , Rabih Halwani 21 , Rie Fukuhara 22 , Gregory A Smith 23 , Veronica Galvan 16 , Masad J Damha 18 , Saleh Al-Muhsen 21 , Yuval Itan 24 , Jef D Boeke 10 , Luigi D Notarangelo 15 , Lorenz Studer 12 , Masao Kobayashi 6 , Luisa Diogo 25 , William G Fairbrother 26 , Laurent Abel 1 , Brad R Rosenberg 27 , P John Hart 28 , Amos Etzioni 29 , Jean-Laurent Casanova 30
Affiliation  

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.

中文翻译:


患有脑干病毒感染的人类 RNA 套索代谢的先天性错误。



通常是良性的病毒有时会侵入其他健康儿童的脑干。我们报告了来自不同种族的无关患者的双等位基因 DBR1 突变,这些患者均患有单纯疱疹病毒 1 (HSV1)、流感病毒或诺如病毒引起的脑干感染。 DBR1 编码唯一已知的 RNA 套索脱支酶。我们发现 DBR1 表达无处不在,但在脊髓和脑干中表达最强。我们还表明,所有 DBR1 突变等位基因在表达和功能方面均严重低效。 DBR1突变患者的成纤维细胞比对照细胞含有更高的RNA套索水平,这种差异在HSV1感染期间变得更加明显。最后,我们发现患者的成纤维细胞对 HSV1 高度敏感。 RNA 套索积累和病毒易感性由野生型 DBR1 拯救。常染色体隐性遗传、部分 DBR1 缺陷是人类脑干病毒感染的基础,通过破坏对病毒的组织特异性和细胞内在免疫力。
更新日期:2018-02-22
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