Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

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.

• Authors: Angeliki Giannelou, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones S Abu-Asab, Kris Ylaya, Deborah L Stone, Anna Sediva, Rola Sleiman, Lucie Sramkova, Deepika Bhatla, Elisavet Serti, Wanxia Li Tsai, Dan Yang, Kevin Bishop, Blake Carrington, Wuhong Pei, Natalie Deuitch, Stephen Brooks, Jehad H Edwan, Sarita Joshi, Seraina Prader, Daniela Kaiser, William C Owen, Abdullah Al Sonbul, Yu Zhang, Julie E Niemela, Shawn M Burgess, Manfred Boehm, Barbara Rehermann, JaeJin Chae, Martha M Quezado, Amanda K Ombrello, Rebecca H Buckley, Alexi A Grom, Elaine F Remmers, Jana M Pachlopnik, Helen C Su, Gustavo Gutierrez-Cruz, Stephen M Hewitt, Raman Sood, Kimberly Risma, Katherine R Calvo, Sergio D Rosenzweig, Massimo Gadina, Markus Hafner, Hong-Wei Sun, Daniel L Kastner, Ivona Aksentijevich
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 77 Issue 4 Pg. 612-619 (04 2018) ISSN: 1468-2060 [Electronic] England
• PMID: 29358286 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• TNF protein, human
• Tumor Necrosis Factor-alpha
• RNA, Transfer
• Nucleotidyltransferases
• TRNT1 protein, human

Topics

• Adult
• Anemia, Sideroblastic (blood, genetics)
• Anti-Inflammatory Agents (therapeutic use)
• Child
• Child, Preschool
• Cytokines (blood, genetics)
• Developmental Disabilities (genetics)
• Female
• Genetic Diseases, X-Linked (blood, genetics)
• Humans
• Immunologic Deficiency Syndromes (genetics)
• Immunophenotyping
• Male
• Mutation
• Nucleotidyltransferases (genetics)
• Pedigree
• Phenotype
• RNA, Transfer (genetics)
• Tumor Necrosis Factor-alpha (analysis, antagonists & inhibitors)
• Exome Sequencing