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 - Funding Information:
We thank the patients and their families; the members of the laboratory for helpful discussions; Tatiana Kochetkov for technical assistance; Lei Shang, Benedetta Bigio, Vimel Ratinna, Bertrand Boisson, and Jason Banfelder for computational assistance; and Dominick Papandrea, Cécile Patissier, and Yelena Nemirovskaya for administrative assistance. This work was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) , Clinical and Translational Science Award program grant number 8UL1TR000043 , NIH grants 5R21NS084255 , 5R01AI088364 and 5R01NS072381 , the ANR grants HSEIEIER and ANR-10-LABX-62-IBEID , an award from D.I.M. Pathologies infectieuses humaines ( DIM150012 ), a grant from Starr Foundation Tri-Institutional Stem Cell Initiative ( 2014-005 ), a Grant from the Japan Society for the Promotion of Science ( 16H05355 ), a grant from the Japanese Agency for Medical Research and Development, AMED , the Rockefeller University , INSERM , Paris Descartes University , and the St Giles Foundation . N.E.C. was supported by NIH T-32 AG021890 . A.B was supported in part by EMBO ALTF 280-2016 . V.G. is supported by NIH/NIA R01AG057964-01 , US Department of Veterans Affairs I01 BX002211-01A2 , the William & Ella Owens Medical Research Foundation , and the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer’s Fund . K.D. and L.D.N. are supported by the NIH . P.J.H is supported by US Department of Veterans Affairs I01 BX0025801 . B.R.R. was supported in part by the NIH and then John C. Whitehead Presidential Fellowship .
Funding Information:
We thank the patients and their families; the members of the laboratory for helpful discussions; Tatiana Kochetkov for technical assistance; Lei Shang, Benedetta Bigio, Vimel Ratinna, Bertrand Boisson, and Jason Banfelder for computational assistance; and Dominick Papandrea, Cécile Patissier, and Yelena Nemirovskaya for administrative assistance. This work was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Clinical and Translational Science Award program grant number 8UL1TR000043, NIH grants 5R21NS084255, 5R01AI088364 and 5R01NS072381, the ANR grants HSEIEIER and ANR-10-LABX-62-IBEID, an award from D.I.M. Pathologies infectieuses humaines (DIM150012), a grant from Starr Foundation Tri-Institutional Stem Cell Initiative (2014-005), a Grant from the Japan Society for the Promotion of Science (16H05355), a grant from the Japanese Agency for Medical Research and Development, AMED, the Rockefeller University, INSERM, Paris Descartes University, and the St Giles Foundation. N.E.C. was supported by NIH T-32 AG021890. A.B was supported in part by EMBO ALTF 280-2016. V.G. is supported by NIH/NIA R01AG057964-01, US Department of Veterans Affairs I01 BX002211-01A2, the William & Ella Owens Medical Research Foundation, and the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer's Fund. K.D. and L.D.N. are supported by the NIH. P.J.H is supported by US Department of Veterans Affairs I01 BX0025801. B.R.R. was supported in part by the NIH and then John C. Whitehead Presidential Fellowship.
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
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
VL - 172
SP - 952-965.e18
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -