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; 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

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

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	952-965.e18
Journal	Cell
Volume	172
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2018.02.019
State	Published - Feb 22 2018

Keywords

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

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2018.02.019

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Zhang, S. Y., Clark, N. E., Freije, C. A., Pauwels, E., Taggart, A. J., Okada, S., Mandel, H., Garcia, P., Ciancanelli, M. J., Biran, A., Lafaille, F. G., Tsumura, M., Cobat, A., Luo, J., Volpi, S., Zimmer, B., Sakata, S., Dinis, A., Ohara, O., ... Casanova, J. L. (2018). Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell, 172(5), 952-965.e18. https://doi.org/10.1016/j.cell.2018.02.019

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, 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. 952-965.e18. https://doi.org/10.1016/j.cell.2018.02.019

@article{31666af576db452f93c8d4ec48a8fa4d,

title = "Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection",

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{\textquoteright} 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.",

keywords = "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",

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

note = "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, C{\'e}cile 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{\textquoteright}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, C{\'e}cile 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: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = feb,

day = "22",

doi = "10.1016/j.cell.2018.02.019",

language = "English (US)",

volume = "172",

pages = "952--965.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

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

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 -

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

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