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Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors
A. Giannelou, H. Wang, Q. Zhou, YH. Park, MS. Abu-Asab, K. Ylaya, DL. Stone, A. Sediva, R. Sleiman, L. Sramkova, D. Bhatla, E. Serti, WL. Tsai, D. Yang, K. Bishop, B. Carrington, W. Pei, N. Deuitch, S. Brooks, JH. Edwan, S. Joshi, S. Prader, D....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, Research Support, N.I.H., Intramural
NLK
ProQuest Central
od 1939-01-01 do Před 6 měsíci
Health & Medicine (ProQuest)
od 1939-01-01 do Před 6 měsíci
Family Health Database (ProQuest)
od 1939-01-01 do Před 6 měsíci
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- antiflogistika terapeutické užití MeSH
- cytokiny krev genetika MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- genetické nemoci vázané na chromozom X krev genetika MeSH
- imunofenotypizace MeSH
- lidé MeSH
- mutace * MeSH
- nukleotidyltransferasy genetika MeSH
- předškolní dítě MeSH
- RNA transferová genetika MeSH
- rodokmen MeSH
- sekvenování exomu MeSH
- sideroblastická anemie krev genetika MeSH
- syndromy imunologické nedostatečnosti genetika MeSH
- TNF-alfa analýza antagonisté a inhibitory MeSH
- vývojové poruchy u dětí genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Intramural MeSH
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.
Department of Immunology Charles University and University Hospital Motol Prague Czech Republic
Department of Immunology University Children's Hospital Zurich Zurich Switzerland
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 Pathology National Cancer Institute Bethesda Maryland USA
Section of Histopathology National Eye Institute Bethesda Maryland USA
Zebrafish Core National Human Genome Research Institute Bethesda Maryland USA
Citace poskytuje Crossref.org
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- $a Giannelou, Angeliki $u Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA. Rheumatology Fellowship and Training Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
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- $a Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors / $c A. Giannelou, H. Wang, Q. Zhou, YH. Park, MS. Abu-Asab, K. Ylaya, DL. Stone, A. Sediva, R. Sleiman, L. Sramkova, D. Bhatla, E. Serti, WL. Tsai, D. Yang, K. Bishop, B. Carrington, W. Pei, N. Deuitch, S. Brooks, JH. Edwan, S. Joshi, S. Prader, D. Kaiser, WC. Owen, AA. Sonbul, Y. Zhang, JE. Niemela, SM. Burgess, M. Boehm, B. Rehermann, J. Chae, MM. Quezado, AK. Ombrello, RH. Buckley, AA. Grom, EF. Remmers, JM. Pachlopnik, HC. Su, G. Gutierrez-Cruz, SM. Hewitt, R. Sood, K. Risma, KR. Calvo, SD. Rosenzweig, M. Gadina, M. Hafner, HW. Sun, DL. Kastner, I. Aksentijevich,
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