TY - JOUR
T1 - Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection
AU - Zhang, Shen Ying
AU - Clark, Nathaniel E.
AU - Freije, Catherine A.
AU - Pauwels, Elodie
AU - Taggart, Allison J.
AU - Okada, Satoshi
AU - Mandel, Hanna
AU - Garcia, Paula
AU - Ciancanelli, Michael J.
AU - Biran, Anat
AU - Lafaille, Fabien G.
AU - Tsumura, Miyuki
AU - Cobat, Aurélie
AU - Luo, Jingchuan
AU - Volpi, Stefano
AU - Zimmer, Bastian
AU - Sakata, Sonoko
AU - Dinis, Alexandra
AU - Ohara, Osamu
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, 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.
AU - Abel, Laurent
AU - Rosenberg, Brad R.
AU - Hart, P. John
AU - Etzioni, Amos
AU - Casanova, Jean Laurent
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/2/22
Y1 - 2018/2/22
N2 - 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.
AB - 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.
KW - DBR1
KW - RNA lariat debranching
KW - brainstem
KW - viral encephalitis
KW - Introns/genetics
KW - RNA Nucleotidyltransferases/chemistry
KW - Toll-Like Receptor 3/metabolism
KW - Humans
KW - Male
KW - Fibroblasts/metabolism
KW - Female
KW - Mutant Proteins/metabolism
KW - Interferons/metabolism
KW - Amino Acid Sequence
KW - Brain Stem/metabolism
KW - Mutation/genetics
KW - Open Reading Frames/genetics
KW - Brain Diseases, Metabolic, Inborn/genetics
KW - Encephalitis, Viral/genetics
KW - Escherichia coli/metabolism
KW - Herpesvirus 1, Human
KW - RNA/chemistry
KW - Animals
KW - Virus Replication
KW - Pedigree
KW - Alleles
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85042390540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042390540&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.02.019
DO - 10.1016/j.cell.2018.02.019
M3 - Article
C2 - 29474921
AN - SCOPUS:85042390540
SN - 0092-8674
VL - 172
SP - 952-965.e18
JO - Cell
JF - Cell
IS - 5
ER -