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Extended report
Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors
  1. Angeliki Giannelou1,2,
  2. Hongying Wang1,
  3. Qing Zhou1,
  4. Yong Hwan Park1,
  5. Mones S Abu-Asab3,
  6. Kris Ylaya4,
  7. Deborah L Stone1,
  8. Anna Sediva5,
  9. Rola Sleiman6,
  10. Lucie Sramkova7,
  11. Deepika Bhatla8,
  12. Elisavet Serti9,
  13. Wanxia Li Tsai10,
  14. Dan Yang11,
  15. Kevin Bishop12,
  16. Blake Carrington12,
  17. Wuhong Pei12,
  18. Natalie Deuitch1,
  19. Stephen Brooks13,
  20. Jehad H Edwan14,
  21. Sarita Joshi15,
  22. Seraina Prader16,
  23. Daniela Kaiser17,
  24. William C Owen18,
  25. Abdullah Al Sonbul19,
  26. Yu Zhang20,
  27. Julie E Niemela21,
  28. Shawn M Burgess12,
  29. Manfred Boehm11,
  30. Barbara Rehermann9,
  31. JaeJin Chae1,
  32. Martha M Quezado22,
  33. Amanda K Ombrello1,
  34. Rebecca H Buckley23,
  35. Alexi A Grom24,
  36. Elaine F Remmers1,
  37. Jana M Pachlopnik16,
  38. Helen C Su20,
  39. Gustavo Gutierrez-Cruz25,
  40. Stephen M Hewitt4,
  41. Raman Sood12,
  42. Kimberly Risma26,
  43. Katherine R Calvo21,
  44. Sergio D Rosenzweig21,
  45. Massimo Gadina10,
  46. Markus Hafner24,
  47. Hong-Wei Sun13,
  48. Daniel L Kastner1,
  49. Ivona Aksentijevich1
  1. 1 Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  2. 2 Rheumatology Fellowship and Training Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  3. 3 Section of Histopathology, National Eye Institute, Bethesda, Maryland, USA
  4. 4 Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA
  5. 5 Department of Immunology Charles, University and University Hospital Motol, Prague, Czech Republic
  6. 6 Dr. Sulaiman Al Habib Al Rayan Hospital, Riyadh, Saudi Arabia
  7. 7 Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
  8. 8 SSM Health Cardinal Glennon Children’s Hospital, Saint Louis University School of Medicine, St. Louis, Missouri, USA
  9. 9 Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
  10. 10 Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  11. 11 Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
  12. 12 Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, USA
  13. 13 Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  14. 14 Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  15. 15 Department of Pathology, The Cleveland Clinic, Cleveland, Ohio, USA
  16. 16 Department of Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
  17. 17 Department of Pediatric Rheumatology, Children’s Hospital, Lucerne, Switzerland
  18. 18 Children’s Cancer and Blood Disorders Center, Children’s Hospital of the King’s Daughters, Norfolk, Virginia, USA
  19. 19 King Faisal Specialist Hospital &Research Center, Riyadh, Saudi Arabia
  20. 20 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  21. 21 Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
  22. 22 Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
  23. 23 Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina, USA
  24. 24 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  25. 25 Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  26. 26 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Dr Ivona Aksentijevich, National Human Genome Research Institute, Bethesda, Maryland 20892-2152, USA; aksentii{at}mail.nih.gov

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.

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

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Footnotes

  • 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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