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 Reino & 29 others Kerry 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 Hart, 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 journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)952-956.e18
JournalCell
Volume172
Issue number5
DOIs
StatePublished - Feb 22 2018

Fingerprint

Virus Diseases
Viruses
Metabolism
Brain Stem
RNA
Human Herpesvirus 1
Fibroblasts
Norovirus
Orthomyxoviridae
Level control
Immunity
Spinal Cord
Alleles
Mutation
Tissue
Infection

Keywords

  • brainstem
  • DBR1
  • RNA lariat debranching
  • viral encephalitis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, S. Y., Clark, N. E., Freije, C. A., Pauwels, E., Taggart, A. J., Okada, S., ... Casanova, J. L. (2018). Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell, 172(5), 952-956.e18. https://doi.org/10.1016/j.cell.2018.02.019

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

In: Cell, Vol. 172, No. 5, 22.02.2018, p. 952-956.e18.

Research output: Contribution to journalArticle

Zhang, SY, Clark, NE, Freije, CA, Pauwels, E, Taggart, AJ, Okada, S, Mandel, H, Garcia, P, Ciancanelli, MJ, Biran, A, Lafaille, FG, Tsumura, M, Cobat, A, Luo, J, Volpi, S, Zimmer, B, Sakata, S, Dinis, A, Ohara, O, Garcia Reino, EJ, Dobbs, K, Hasek, M, Holloway, SP, McCammon, K, Hussong, SA, DeRosa, N, Van Skike, CE, Katolik, A, Lorenzo, L, Hyodo, M, Faria, E, Halwani, R, Fukuhara, R, Smith, GA, Galvan Hart, V, Damha, MJ, Al-Muhsen, S, Itan, Y, Boeke, JD, Notarangelo, LD, Studer, L, Kobayashi, M, Diogo, L, Fairbrother, WG, Abel, L, Rosenberg, BR, Hart, PJ, Etzioni, A & Casanova, JL 2018, 'Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection', Cell, vol. 172, no. 5, pp. 952-956.e18. https://doi.org/10.1016/j.cell.2018.02.019
Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S et al. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell. 2018 Feb 22;172(5):952-956.e18. https://doi.org/10.1016/j.cell.2018.02.019
Zhang, Shen Ying ; Clark, Nathaniel E. ; Freije, Catherine A. ; Pauwels, Elodie ; Taggart, Allison J. ; Okada, Satoshi ; Mandel, Hanna ; Garcia, Paula ; Ciancanelli, Michael J. ; Biran, Anat ; Lafaille, Fabien G. ; Tsumura, Miyuki ; Cobat, Aurélie ; Luo, Jingchuan ; Volpi, Stefano ; Zimmer, Bastian ; Sakata, Sonoko ; Dinis, Alexandra ; Ohara, Osamu ; Garcia Reino, Eduardo J. ; Dobbs, Kerry ; Hasek, Mary ; Holloway, Stephen P. ; McCammon, Karen ; Hussong, Stacy A. ; DeRosa, Nicholas ; Van Skike, Candice E. ; Katolik, Adam ; Lorenzo, Lazaro ; Hyodo, Maki ; Faria, Emilia ; Halwani, Rabih ; Fukuhara, Rie ; Smith, Gregory A. ; Galvan Hart, Veronica ; Damha, Masad J. ; Al-Muhsen, Saleh ; Itan, Yuval ; Boeke, Jef D. ; Notarangelo, Luigi D. ; Studer, Lorenz ; Kobayashi, Masao ; Diogo, Luisa ; Fairbrother, William G. ; Abel, Laurent ; Rosenberg, Brad R. ; Hart, P. John ; Etzioni, Amos ; Casanova, Jean Laurent. / Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. In: Cell. 2018 ; Vol. 172, No. 5. pp. 952-956.e18.
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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.",
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AU - Freije, Catherine A.

AU - Pauwels, Elodie

AU - Taggart, Allison J.

AU - Okada, Satoshi

AU - Mandel, Hanna

AU - Garcia, Paula

AU - Ciancanelli, Michael J.

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AU - Dinis, Alexandra

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AU - Garcia Reino, Eduardo J.

AU - Dobbs, Kerry

AU - Hasek, Mary

AU - Holloway, Stephen P.

AU - McCammon, Karen

AU - Hussong, Stacy A.

AU - DeRosa, Nicholas

AU - Van Skike, Candice E.

AU - Katolik, Adam

AU - Lorenzo, Lazaro

AU - Hyodo, Maki

AU - Faria, Emilia

AU - Halwani, Rabih

AU - Fukuhara, Rie

AU - Smith, Gregory A.

AU - Galvan Hart, Veronica

AU - Damha, Masad J.

AU - Al-Muhsen, Saleh

AU - Itan, Yuval

AU - Boeke, Jef D.

AU - Notarangelo, Luigi D.

AU - Studer, Lorenz

AU - Kobayashi, Masao

AU - Diogo, Luisa

AU - Fairbrother, William G.

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AU - Etzioni, Amos

AU - Casanova, Jean Laurent

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