Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Hypomorphic mutations in the TRNT1gene result in a syndrome of sideroblastic anemia, immunodeficiency, periodic fevers and developmental delay (SIFD). The TRNT1 enzyme is essential for tRNA maturation and regulation, aminoacylation and protein synthesis. Complete deficiency is incompatible with life.
Methods: Genetic studies included whole exome sequencing and candidate gene screening. Patient cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
Results: We have identified 9 patients with biallelic missense mutations in TRNT1. 5 out of 9 mutations have not been reported. Patients suffered from recurrent fevers, variable degrees of immunodeficiency and a combination of inflammatory and degenerative disease. Inflammatory cytokines, mainly IL-6, IFN-g and IFN-induced cytokines were found elevated in the serum and in stimulated cells ex vivo. Deep tRNA sequencing of patients’ fibroblasts showed that more than two third of patient’s mature tRNAs were decreased compared to controls. EM microscopy of bone marrow and skin biopsy tissues showed striking abnormalities across all cell types, including pyknotic nuclei, disorganized cytoskeleton, extranuclear DNA, and abnormal mitochondria. We observed a mix of necroptotic and normal appearing cells in all tissues. Autophagosomal vesicles were observed intracellularly and in the serum. Intriguingly, the patient with the most severe inflammatory phenotype had evidence by EM of different, coexisting, types of cell death, proteinaceous substance and cellular debris in the bone marrow stroma. In agreement, gene expression profiling from patients’ fibroblasts and whole blood, showed that the top differentially expressed genes belonged to pathways involving DNA damage control, protein trafficking, acute phase response, and extracellular tissue homeostasis. By immunoprecipitation, we further determined that patients’ fibroblasts have malfunction in the maintenance of proteostasis as evidenced by dysregulation in proteasome and autophagy function, and accumulation of ubiquitinated proteins. No effective treatment has been described for this syndrome so far. Preliminary experience in our cohort suggests that treatment with a TNF-a inhibitor is beneficial for suppressing inflammation, stabilizing anemia and improving growth.
Conclusion: Mutations of TRNT1 enzyme lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Future study of this disease will likely give new insights at cellular level about the role of protein homeostasis in immune cell development and susceptibility to inflammation in general. It might also provide more insights for targeted therapies of inflammatory diseases linked to protein degradation.
To cite this abstract in AMA style:Giannelou A, Zhou Q, Wang H, Mones AA, Sun HW, Stone DL, Ombrello AK, Tsai WL, Brooks S, Edwan JH, Risma K, Sramkova L, Al Sonbul A, Joshi S, Su HC, Barron K, Gadina MG, Gutierrez-Cruz G, Hafner M, Aksentijevich I, Kastner DL. Proteostasis Dysregulation and Autoinflammation in Patients with TRNT1 Deficiency [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/proteostasis-dysregulation-and-autoinflammation-in-patients-with-trnt1-deficiency/. Accessed November 27, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proteostasis-dysregulation-and-autoinflammation-in-patients-with-trnt1-deficiency/