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.

Biodata Mining and Discovery Section National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda Maryland USA

Children's Cancer and Blood Disorders Center Children's Hospital of the King's Daughters Norfolk Virginia USA

Department of Immunology Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology University Children's Hospital Zurich Zurich Switzerland

Department of Laboratory Medicine National Institutes of Health Clinical Center Bethesda Maryland USA

Department of Pathology The Cleveland Clinic Cleveland Ohio USA

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic

Department of Pediatric Rheumatology Children's Hospital Lucerne Switzerland

Departments of Pediatrics and Immunology Duke University Medical Center Durham North Carolina USA

Division of Allergy and Immunology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA

Division of Rheumatology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA

Dr Sulaiman Al Habib Al Rayan Hospital Riyadh Saudi Arabia

Experimental Pathology Laboratory National Cancer Institute Bethesda Maryland USA

Inflammatory Disease Section National Human Genome Research Institute Bethesda Maryland USA

King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia

Laboratory of Cardiovascular Regenerative Medicine National Heart Lung and Blood Institute Bethesda Maryland USA

Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases Bethesda Maryland USA

Laboratory of Muscle Stem Cells and Gene Regulation National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda Maryland USA

Laboratory of Pathology National Cancer Institute Bethesda Maryland USA

Liver Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases Bethesda Maryland USA

Pediatric Translational Research Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda Maryland USA

Rheumatology Fellowship and Training Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda Maryland USA

Section of Histopathology National Eye Institute Bethesda Maryland USA

SSM Health Cardinal Glennon Children's Hospital Saint Louis University School of Medicine St Louis Missouri USA

Translational Immunology Section National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda Maryland USA

Zebrafish Core National Human Genome Research Institute Bethesda Maryland USA

Ann Rheum Dis. 2019 Aug;78(8):e86. doi: 10.1136/annrheumdis-2018-213745. PubMed

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