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.

• Klíčová slova
• TRNT1, TNF inhibitors, anti-TNF therapy, autoinflammation, congenital sideroblastic anemia with immunodeficiency, developmental delay (SIFD), fevers, tRNA,
• 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
• Názvy látek
• antiflogistika MeSH
• cytokiny MeSH
• nukleotidyltransferasy MeSH
• RNA transferová MeSH
• TNF protein, human MeSH Prohlížeč
• TNF-alfa MeSH
• TRNT1 protein, human MeSH Prohlížeč