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Cell. 2018 Feb 22;172(5):952-965.e18. doi: 10.1016/j.cell.2018.02.019.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris 75015, France; Paris Descartes University, Imagine Institute, Paris 75015, France. Electronic address: shzh289@rockefeller.edu.
2
Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
3
Program in Immunogenomics, The Rockefeller University, New York, NY 10065, USA.
4
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
5
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
6
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima 734-8553, Japan.
7
Metabolic Unit, Ruth Children's Hospital, Rambam Health Care Campus, Haifa 31096, Israel; Rappaport Faculty of Medicine, Haifa 31096, Israel.
8
Child Developmental Center, Pediatric Hospital, Hospital and University Center of Coimbra, Coimbra 3000-602, Portugal.
9
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris 75015, France; Paris Descartes University, Imagine Institute, Paris 75015, France.
10
Department of Molecular Biology & Genetics, JHU School of Medicine, Baltimore, MD 21205, USA; Institute for Systems Genetics, NYU Langone Health, New York 10016, NY, USA.
11
Pediatric and Rheumatology Clinic, Center for Autoinflammatory Diseases and Immunodeficiencies, Istituto Giannina Gaslini and University of Genoa, Genoa 16100, Italy.
12
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA.
13
Pediatric Intensive Care Unit, Pediatric Hospital, Hospital and University Center of Coimbra, Coimbra 3000-075, Portugal.
14
Department of Technology Development, Kazusa DNA Research Institute, Chiba 292-0818, Japan; Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
15
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-1456, USA.
16
Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX 78229, USA; South Texas Veterans Health Care System, Department of Veterans Affairs, TX 78229, USA.
17
Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX 78229, USA.
18
Department of Chemistry, McGill University, Montréal, QC H3A0B8, Canada.
19
Department of Obstetrics and Gynecology, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima 734-8553, Japan.
20
Immuno-Allergy Department, Hospital and University of Coimbra, Coimbra 3000-075, Portugal.
21
Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
22
Department of Neonatology, Hiroshima Prefectural Hospital, Hiroshima 734-8115, Japan.
23
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
24
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
25
Pediatric Hospital of Coimbra, Coimbra 3000-075, Portugal.
26
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA; Hassenfeld Child Health Innovation Institute, Brown University, Providence, RI 02912, USA.
27
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris 75015, France; Paris Descartes University, Imagine Institute, Paris 75015, France.
28
Program in Immunogenomics, The Rockefeller University, New York, NY 10065, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
29
Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, Department of Veterans Affairs, TX 78229, USA; X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
30
Rappaport Faculty of Medicine, Haifa 31096, Israel; Immunology Unit, Ruth Children's Hospital, Haifa 31096, Israel.
31
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris 75015, France; Paris Descartes University, Imagine Institute, Paris 75015, France; Howard Hughes Medical Institute, New York, NY 10065, USA; Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris 75015, France.

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.

KEYWORDS:

DBR1; RNA lariat debranching; brainstem; viral encephalitis

PMID:
29474921
PMCID:
PMC5886375
DOI:
10.1016/j.cell.2018.02.019
[Indexed for MEDLINE]
Free PMC Article

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