Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection

Shen Ying Zhang, Nathaniel E. Clark, Catherine A. Freije, Elodie Pauwels, Allison J. Taggart, Satoshi Okada, Hanna Mandel, Paula Garcia, Michael J. Ciancanelli, Anat Biran, Fabien G. Lafaille, Miyuki Tsumura, Aurélie Cobat, Jingchuan Luo, Stefano Volpi, Bastian Zimmer, Sonoko Sakata, Alexandra Dinis, Osamu Ohara, Eduardo J. Garcia ReinoKerry Dobbs, Mary Hasek, Stephen P. Holloway, Karen McCammon, Stacy A. Hussong, Nicholas DeRosa, Candice E. Van Skike, Adam Katolik, Lazaro Lorenzo, Maki Hyodo, Emilia Faria, Rabih Halwani, Rie Fukuhara, Gregory A. Smith, Veronica Galvan, Masad J. Damha, Saleh Al-Muhsen, Yuval Itan, Jef D. Boeke, Luigi D. Notarangelo, Lorenz Studer, Masao Kobayashi, Luisa Diogo, William G. Fairbrother, Laurent Abel, Brad R. Rosenberg, P. John Hart, Amos Etzioni, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)952-965.e18
Issue number5
StatePublished - Feb 22 2018


  • DBR1
  • RNA lariat debranching
  • brainstem
  • viral encephalitis
  • Introns/genetics
  • RNA Nucleotidyltransferases/chemistry
  • Toll-Like Receptor 3/metabolism
  • Humans
  • Male
  • Fibroblasts/metabolism
  • Female
  • Mutant Proteins/metabolism
  • Interferons/metabolism
  • Amino Acid Sequence
  • Brain Stem/metabolism
  • Mutation/genetics
  • Open Reading Frames/genetics
  • Brain Diseases, Metabolic, Inborn/genetics
  • Encephalitis, Viral/genetics
  • Escherichia coli/metabolism
  • Herpesvirus 1, Human
  • RNA/chemistry
  • Animals
  • Virus Replication
  • Pedigree
  • Alleles
  • Mice

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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