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.
- congenital sideroblastic anemia with immunodeficiency
- developmental delay (SIFD)
- TNF inhibitors
- anti-TNF therapy
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Handling editor Josef S Smolen
Contributors AG, QZ, DLK and IA conceived the study. DLS, AS, RS, LS, DB, SJ, SP, DK, WCO, AAS, AKO, RHB, AAG, JMP, HCS and KR provided clinical data and patient material. AG, HW, QZ, YWP, MSA-A, KY, ES, WLT, DY, KB, BC, WP, ND, JHE, JC, EFR and GG-C performed experiments. AG, SB, YZ, JEN, SMB, MB, BR, MMQ, SMH, RS, KRC, SDR, MG, MH, H-WS and IA performed data analysis. AG and IA wrote the first and last draft of the manuscript. DLK and EFR critically revised the manuscript. All authors approved the final version of the manuscript.
Funding This research was supported by the Intramural Research Programs of the National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Allegy and Infectious Diseases (NIAID), National Cancer Institute (NCI), National Eye Institute (NEI), Institute National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Clinical Center.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The present study was approved by by the NIDDK/NIAMS Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available from the corresponding author upon request.
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