Immune Dysregulation in Patients with TRNT1 Deficiency

Angeliki Giannelou¹, Qing Zhou², Hong-Wei Sun³, Dan Yang⁴, Susan Moir⁵, Jehad H. Edwan³, Wanxia L. Tsai³, Elisavet Serti⁶, Monique Stoffels², Deborah L. Stone⁷, Amanda K. Ombrello⁷, Karyl Barron⁵, Helen C. Su⁵, Abdullah Al Sonbul⁸, Sarita Joshi⁹, Kimberly Risma¹⁰, Lucie Sramkova¹¹, Martha M. Quezado¹², Katherine Calvo¹³, Abu-Asab Mones¹⁴, Gustavo Gutierrez-Cruz³, Massimo G. Gadina³, Markus Hafner³, Ivona Aksentijevich^2,15 and Daniel Kastner², ¹National Human Genome Research Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ²NIH/NHGRI, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, Bethesda, MD, ³National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁴National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, ⁵National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, ⁶Immunology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, ⁷National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ⁸King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, ⁹Nationwide Children's Hospital, Columbus, OH, ¹⁰Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ¹¹Charles University 2nd Faculty of Medicine and UH Motol, Prague, Czech Republic, ¹²Laboratory of Pathology/National Cancer Institute, National Institutes of Health, Bethesda, MD, ¹³Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, ¹⁴National Eye Institute, National Institutes of Health, Bethesda, MD, ¹⁵Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Autoinflammatory Disease and Gene Expression

Session Information

Date: Monday, November 9, 2015

Title: Genetics, Genomics and Proteomics

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Next generation sequencing has led to the discovery of new diseases and molecules regulating immune function. Hypomorphic mutations in the TRNT1 gene cause a syndrome of sideroblastic anemia, immunodeficiency, periodic fevers and developmental delay, also known as SIFD. The TRNT1 enzyme catalyzes an essential step for tRNA maturation and protein synthesis, however, the underlying disease mechanisms are largely unknown. We aim to characterize the mechanisms of inflammation in this disease.

Methods: Whole exome sequencing or candidate gene screening was performed in two families, each with two affected siblings, and in three sporadic patients. Patient cells and tissue were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping through multicolor flow cytometry, H&E, immunohistochemistry and electron microscopy.

Results:

We identified seven patients with biallelic missense homozygous or compound heterozygous mutations in TRNT1. Four out of six mutations have not been reported. Three patients died of multiorgan failure. Two apparently unrelated patients shared the same genotype and had similar clinical presentation. Deep sequencing of tRNAs isolated from patients’ fibroblasts showed a significant down-regulation of mature tRNAs when compared to healthy controls. RNA-sequencing of patients’ whole blood revealed up-regulation of neutrophil-related genes. Consistent with these data, lesional biopsies from two patients’ colon showed cryptitis with neutrophilic infiltration. Cultured patients’ macrophages showed increased expression of proinflammatory cytokines IL-6, TNF-a, IL-1b, and accordingly, monocytes displayed increased phosphorylation of STAT3 ex vivo, possibly IL-6 induced, compared to monocytes isolated from healthy donors. Patients had variable degrees of B cell immunodeficiency with an increased population of immature B cells in the peripheral blood. Four patients had a bone marrow examination that revealed a markedly increased number of immature CD10⁺ CD20^–B cells, and at the same time a decreased mature B cell population. Electron microscopy of BM smears showed evidence for abnormal morphology of blood vessels and endothelial cells, serum leakage and cellular debris in the stroma. Lymphocytes and monocytes displayed abnormal shape and degenerated mitochondria. Three patients have been on treatment with a TNF-a inhibitor that has shown promising results in attenuating the systemic inflammation and stabilizing the anemia.

Conclusion: Hypomorphic mutations in TRNT1 are associated with a new, often severe, autoinflammatory disease manifesting a pleiotropic clinical phenotype. Given the essential function and ubiquitous expression of TRNT1, multiple cell types are affected. Myeloid cells, macrophages and neutrophils, might play an important role in mediating inflammation. Further studies may lead to the discovery of a new pathway regulating immune function.

Disclosure: A. Giannelou, None; Q. Zhou, None; H. W. Sun, None; D. Yang, None; S. Moir, None; J. H. Edwan, None; W. L. Tsai, None; E. Serti, None; M. Stoffels, None; D. L. Stone, None; A. K. Ombrello, None; K. Barron, None; H. C. Su, None; A. Al Sonbul, None; S. Joshi, None; K. Risma, None; L. Sramkova, None; M. M. Quezado, None; K. Calvo, None; A. A. Mones, None; G. Gutierrez-Cruz, None; M. G. Gadina, None; M. Hafner, None; I. Aksentijevich, None; D. Kastner, None.

To cite this abstract in AMA style:

Giannelou A, Zhou Q, Sun HW, Yang D, Moir S, Edwan JH, Tsai WL, Serti E, Stoffels M, Stone DL, Ombrello AK, Barron K, Su HC, Al Sonbul A, Joshi S, Risma K, Sramkova L, Quezado MM, Calvo K, Mones AA, Gutierrez-Cruz G, Gadina MG, Hafner M, Aksentijevich I, Kastner D. Immune Dysregulation in Patients with TRNT1 Deficiency [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/immune-dysregulation-in-patients-with-trnt1-deficiency/. Accessed .

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