Inborn errors of RNA lariat metabolism in humans with brainstem viral infection Journal Article
| Authors: | Zhang, S. Y.; Clark, N. E.; Freije, C. A.; Pauwels, E.; Taggart, A. J.; Okada, S.; Mandel, H.; Garcia, P.; Ciancanelli, M. J.; Biran, A.; Lafaille, F. G.; Tsumura, M.; Cobat, A.; Luo, J.; Volpi, S.; Zimmer, B.; Sakata, S.; Dinis, A.; Ohara, O.; Garcia Reino, E. J.; Dobbs, K.; Hasek, M.; Holloway, S. P.; McCammon, K.; Hussong, S. A.; DeRosa, N.; Van Skike, C. E.; Katolik, A.; Lorenzo, L.; Hyodo, M.; Faria, E.; Halwani, R.; Fukuhara, R.; Smith, G. A.; Galvan, V.; Damha, M. J.; Al-Muhsen, S.; Itan, Y.; Boeke, J. D.; Notarangelo, L. D.; Studer, L.; Kobayashi, M.; Diogo, L.; Fairbrother, W. G.; Abel, L.; Rosenberg, B. R.; Hart, P. J.; Etzioni, A.; Casanova, J. L. |
| Article Title: | Inborn errors of RNA lariat metabolism in humans with brainstem viral infection |
| Abstract: | 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. Autosomal recessive DBR1 deficiency underlies a cellular accumulation of RNA lariats, resulting in patient susceptibility to severe viral infections of the brainstem. © 2018 Elsevier Inc. |
| Keywords: | child; controlled study; human tissue; gene mutation; human cell; nonhuman; animal cell; allele; gene; gene expression; embryo; gene function; rna; fibroblast; virus infection; brain stem; ethnicity; rna metabolism; rna splicing; influenza virus; virus immunity; norovirus; inborn error of metabolism; brainstem; brain infection; human; male; female; priority journal; article; dbr1; rna lariat debranching; viral encephalitis; dbr1 gene; human alphaherpesvirus 1; rna lariat |
| Journal Title: | Cell |
| Volume: | 172 |
| Issue: | 5 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2018-02-22 |
| Start Page: | 952 |
| End Page: | 965.e18 |
| Language: | English |
| DOI: | 10.1016/j.cell.2018.02.019 |
| PROVIDER: | scopus |
| PMCID: | PMC5886375 |
| PUBMED: | 29474921 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
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