Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.
- Giannelou A Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Wang H Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Zhou Q Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Park YH Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Abu-Asab MS Section of Histopathology, National Eye Institute, Bethesda, Maryland, USA.
- Ylaya K Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
- Stone DL Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Sediva A Department of Immunology Charles, University and University Hospital Motol, Prague, Czech Republic.
- Sleiman R Dr. Sulaiman Al Habib Al Rayan Hospital, Riyadh, Saudi Arabia.
- Sramkova L Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
- Bhatla D SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
- Serti E Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
- Tsai WL Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Yang D Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
- Bishop K Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Carrington B Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Pei W Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Deuitch N Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Brooks S Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Edwan JH Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Joshi S Department of Pathology, The Cleveland Clinic, Cleveland, Ohio, USA.
- Prader S Department of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
- Kaiser D Department of Pediatric Rheumatology, Children's Hospital, Lucerne, Switzerland.
- Owen WC Children's Cancer and Blood Disorders Center, Children's Hospital of the King's Daughters, Norfolk, Virginia, USA.
- Sonbul AA King Faisal Specialist Hospital &Research Center, Riyadh, Saudi Arabia.
- Zhang Y Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
- Niemela JE Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
- Burgess SM Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Boehm M Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
- Rehermann B Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
- Chae J Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Quezado MM Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
- Ombrello AK Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Buckley RH Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
- Grom AA Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
- Remmers EF Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Pachlopnik JM Department of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
- Su HC Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
- Gutierrez-Cruz G Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Hewitt SM Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
- Sood R Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Risma K Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
- Calvo KR Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
- Rosenzweig SD Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
- Gadina M Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Hafner M Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
- Sun HW Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
- Kastner DL Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- Aksentijevich I Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
- 2018-01-24
Published in:
- Annals of the rheumatic diseases. - 2018
TRNT1
TNF inhibitors
anti-TNF therapy
autoinflammation
congenital sideroblastic anemia with immunodeficiency
developmental delay (SIFD)
fevers
tRNA
Adult
Anemia, Sideroblastic
Anti-Inflammatory Agents
Child
Child, Preschool
Cytokines
Developmental Disabilities
Female
Genetic Diseases, X-Linked
Humans
Immunologic Deficiency Syndromes
Immunophenotyping
Male
Mutation
Nucleotidyltransferases
Pedigree
Phenotype
RNA, Transfer
Tumor Necrosis Factor-alpha
Whole Exome Sequencing
English
OBJECTIVES
To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.
METHODS
We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
RESULTS
We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.
CONCLUSIONS
Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.
METHODS
We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
RESULTS
We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.
CONCLUSIONS
Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1136/annrheumdis-2017-212401
- PMID 29358286
- Persistent URL
- https://sonar.ch/global/documents/47605
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