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Ann Rheum Dis. 2018 Apr;77(4):612-619. doi: 10.1136/annrheumdis-2017-212401. Epub 2018 Jan 22.

Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

Author information

1
Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
2
Rheumatology Fellowship and Training Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
3
Section of Histopathology, National Eye Institute, Bethesda, Maryland, USA.
4
Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
5
Department of Immunology Charles, University and University Hospital Motol, Prague, Czech Republic.
6
Dr. Sulaiman Al Habib Al Rayan Hospital, Riyadh, Saudi Arabia.
7
Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
8
SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
9
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
10
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
11
Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
12
Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA.
13
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
14
Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
15
Department of Pathology, The Cleveland Clinic, Cleveland, Ohio, USA.
16
Department of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
17
Department of Pediatric Rheumatology, Children's Hospital, Lucerne, Switzerland.
18
Children's Cancer and Blood Disorders Center, Children's Hospital of the King's Daughters, Norfolk, Virginia, USA.
19
King Faisal Specialist Hospital &Research Center, Riyadh, Saudi Arabia.
20
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
21
Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
22
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
23
Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
24
Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
25
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
26
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Abstract

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.

KEYWORDS:

TRNT1 ; TNF inhibitors; anti-TNF therapy; autoinflammation; congenital sideroblastic anemia with immunodeficiency; developmental delay (SIFD); fevers; tRNA

PMID:
29358286
PMCID:
PMC5890629
DOI:
10.1136/annrheumdis-2017-212401
[Indexed for MEDLINE]
Free PMC Article

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