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; Aurelie Cobat; Jingchuan Luo; Stefano Volpi; Bastian Zimmer; Sonoko Sakata; Alexandra Dinis; Osamu Ohara; Eduardo J. Garcia Reino; 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; 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

doi:10.1016/j.cell.2018.02.019

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

Journal article

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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, …

Cell, Vol.172(5), pp.952-965.e18

22/02/2018

DOI: https://doi.org/10.1016/j.cell.2018.02.019

PMCID: PMC5886375

PMID: 29474921

Abstract

Biochemistry & Molecular Biology

Cell Biology

Life Sciences & Biomedicine

Science & Technology

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.

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Title: Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection
Creators - without role: Shen-Ying Zhang - Inserm
Nathaniel E. Clark - The University of Texas Health Science Center at San Antonio
Catherine A. Freije - Rockefeller University
Elodie Pauwels - Rockefeller University
Allison J. Taggart - John Brown University
Satoshi Okada - Hiroshima University
Hanna Mandel - Rambam Health Care Campus
Paula Garcia - University of Coimbra
Michael J. Ciancanelli - Rockefeller University
Anat Biran - Rockefeller University
Fabien G. Lafaille - Rockefeller University
Miyuki Tsumura - Hiroshima University
Aurelie Cobat - Inserm
Jingchuan Luo - Johns Hopkins University
Stefano Volpi - Istituto Giannina Gaslini
Bastian Zimmer - Yeshiva University
Sonoko Sakata - Hiroshima University
Alexandra Dinis - University of Coimbra
Osamu Ohara - Kazusa DNA Research Institute
Eduardo J. Garcia Reino - Rockefeller University
Kerry Dobbs - National Institutes of Health
Mary Hasek - Rockefeller University
Stephen P. Holloway - The University of Texas Health Science Center at San Antonio
Karen McCammon - The University of Texas Health Science Center at San Antonio
Stacy A. Hussong - The University of Texas Health Science Center at San Antonio
Nicholas DeRosa - The University of Texas Health Science Center at San Antonio
Candice E. Van Skike - The University of Texas Health Science Center at San Antonio
Adam Katolik - McGill University
Lazaro Lorenzo - Inserm
Maki Hyodo - Hiroshima University
Emilia Faria - University of Coimbra
Rabih Halwani - King Saud University
Rie Fukuhara - Hiroshima Prefectural Hospital
Gregory A. Smith - Northwestern Univ, Dept Microbiol Immunol, Feinberg Sch Med, Chicago, IL 60611 USA
Veronica Galvan - The University of Texas Health Science Center at San Antonio
Masad J. Damha - McGill University
Saleh Al-Muhsen - King Saud University
Yuval Itan - Icahn School of Medicine at Mount Sinai
Jef D. Boeke - Johns Hopkins University
Luigi D. Notarangelo - National Institutes of Health
Lorenz Studer - Yeshiva University
Masao Kobayashi - Hiroshima University
Luisa Diogo - University of Coimbra
William G. Fairbrother - John Brown University
Laurent Abel - Rockefeller University
Brad R. Rosenberg - Icahn School of Medicine at Mount Sinai
P. John Hart - The University of Texas Health Science Center at San Antonio
Amos Etzioni - Rambam Health Care Campus
Jean-Laurent Casanova - Rockefeller University
Publication Details: Cell, Vol.172(5), pp.952-965.e18
Publisher: Elsevier
Number of pages: 32
Grant note: Rockefeller University NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA William AMP; Ella Owens Medical Research Foundation INSERM; Institut National de la Sante et de la Recherche Medicale (Inserm) R01AG057964-01 / NIH/NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Japanese Agency for Medical Research and Development 2014-005 / Starr Foundation Tri-lnstitutional Stem Cell Initiative 5R21NS084255; 5R01AI088364; 5R01NS072381; T-32 AG021890 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 16H05355 / Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Paris Descartes University 8UL1TR000043 / National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Clinical and Translational Science Award program AMED ALTF 280-2016 / EMBO; European Molecular Biology Organization (EMBO) John C. Whitehead Presidential Fellowship 17K10112; 16H05355; 16K15528 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) ANR-10-LABX-62-IBEID / ANR grants HSEIEIER; Agence Nationale de la Recherche (ANR) DIM150012 / D.I.M. Pathologies infectieuses humaines I01 BX002211-01A2; I01 BX0025801 / US Department of Veterans Affairs St Giles Foundation
Identifiers: 9946429808331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article