Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

作者：Giannelou Angeliki; Wang Hongying; Zhou Qing; Park Yong Hwan; Abu Asab Mones S; Ylaya Kris; Stone Deborah L; Sediva Anna; Sleiman Rola; Sramkova Lucie; Bhatla Deepika; Serti Elisavet; Tsai Wanxia Li; Yang Dan; Bishop Kevin; Carrington Blake; Pei Wuhong; Deuitch Natalie; Brooks Stephen; Edwan Jehad H; Joshi Sarita; Prader Seraina; Kaiser Daniela; Owen William C; Al Sonbul Abdullah; Zhang Yu; Niemela Julie E; Burgess Shawn M; Boehm Manfred; Rehermann Barbara

来源：Annals of the Rheumatic Diseases, 2018, 77(4): 612-619.

DOI：10.1136/annrheumdis-2017-212401

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

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-) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1 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.

• 出版日期2018-4