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.

中文翻译：

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tRNA 加工异常导致对 TNF 抑制剂有反应的自身炎症综合征

目的 表征最近描述的由 tRNA 加工酶 TRNT1 突变引起的自身炎症性疾病的临床特征、免疫表现和分子机制，并探索细胞因子抑制剂在抑制炎症表型中的用途。方法 我们研究了 9 名具有 TRNT1 双等位基因突变和先天性铁粒幼细胞性贫血伴免疫缺陷、发热和发育迟缓 (SIFD) 综合征的患者。遗传研究包括全外显子组测序（WES）和候选基因筛选。患者的原代细胞用于深度 RNA 和 tRNA 测序、细胞因子分析、免疫表型、免疫印迹和电子显微镜 (EM)。结果 我们在这 9 名患者中发现了 8 种突变，其中 3 种以前与 SIFD 无关。三名患者在幼儿时期死亡。炎症细胞因子，主要是白细胞介素（IL）-6、干扰素γ（IFN-γ）和干扰素诱导的细胞因子在血清中升高，而肿瘤坏死因子（TNF）和IL-1β存在于活动性炎症患者的组织活检中。疾病。患者成纤维细胞的深度 tRNA 测序显示成熟的细胞溶质 tRNA 显着缺乏。骨髓和皮肤活检样本的 EM 显示所有细胞类型均存在显着异常，以及坏死和外观正常的细胞混合。通过免疫沉淀，我们发现了蛋白质清除途径失调的证据。在 4/4 的患者中，使用 TNF 抑制剂治疗抑制了炎症，减少了输血需求并改善了生长。结论 TRNT1 的突变导致严重且通常是致命的综合征，将蛋白质稳态和自身炎症联系起来。生命早期的分子诊断对于启动抗 TNF 治疗至关重要，这可能会预防一些严重的疾病后果。