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Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors
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:...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890629/ https://www.ncbi.nlm.nih.gov/pubmed/29358286 http://dx.doi.org/10.1136/annrheumdis-2017-212401 |
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author | 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 Sonbul, Abdullah Al Zhang, Yu Niemela, Julie E Burgess, Shawn M Boehm, Manfred Rehermann, Barbara Chae, JaeJin Quezado, Martha M Ombrello, Amanda K Buckley, Rebecca H Grom, Alexi A Remmers, Elaine F Pachlopnik, Jana M Su, Helen C Gutierrez-Cruz, Gustavo Hewitt, Stephen M Sood, Raman Risma, Kimberly Calvo, Katherine R Rosenzweig, Sergio D Gadina, Massimo Hafner, Markus Sun, Hong-Wei Kastner, Daniel L Aksentijevich, Ivona |
author_facet | 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 Sonbul, Abdullah Al Zhang, Yu Niemela, Julie E Burgess, Shawn M Boehm, Manfred Rehermann, Barbara Chae, JaeJin Quezado, Martha M Ombrello, Amanda K Buckley, Rebecca H Grom, Alexi A Remmers, Elaine F Pachlopnik, Jana M Su, Helen C Gutierrez-Cruz, Gustavo Hewitt, Stephen M Sood, Raman Risma, Kimberly Calvo, Katherine R Rosenzweig, Sergio D Gadina, Massimo Hafner, Markus Sun, Hong-Wei Kastner, Daniel L Aksentijevich, Ivona |
author_sort | Giannelou, Angeliki |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5890629 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-58906292018-04-16 Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors 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 Sonbul, Abdullah Al Zhang, Yu Niemela, Julie E Burgess, Shawn M Boehm, Manfred Rehermann, Barbara Chae, JaeJin Quezado, Martha M Ombrello, Amanda K Buckley, Rebecca H Grom, Alexi A Remmers, Elaine F Pachlopnik, Jana M Su, Helen C Gutierrez-Cruz, Gustavo Hewitt, Stephen M Sood, Raman Risma, Kimberly Calvo, Katherine R Rosenzweig, Sergio D Gadina, Massimo Hafner, Markus Sun, Hong-Wei Kastner, Daniel L Aksentijevich, Ivona Ann Rheum Dis Basic and Translational Research 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. BMJ Publishing Group 2018-04 2018-01-22 /pmc/articles/PMC5890629/ /pubmed/29358286 http://dx.doi.org/10.1136/annrheumdis-2017-212401 Text en © 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. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Basic and Translational Research 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 Sonbul, Abdullah Al Zhang, Yu Niemela, Julie E Burgess, Shawn M Boehm, Manfred Rehermann, Barbara Chae, JaeJin Quezado, Martha M Ombrello, Amanda K Buckley, Rebecca H Grom, Alexi A Remmers, Elaine F Pachlopnik, Jana M Su, Helen C Gutierrez-Cruz, Gustavo Hewitt, Stephen M Sood, Raman Risma, Kimberly Calvo, Katherine R Rosenzweig, Sergio D Gadina, Massimo Hafner, Markus Sun, Hong-Wei Kastner, Daniel L Aksentijevich, Ivona Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title | Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title_full | Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title_fullStr | Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title_full_unstemmed | Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title_short | Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors |
title_sort | aberrant trna processing causes an autoinflammatory syndrome responsive to tnf inhibitors |
topic | Basic and Translational Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890629/ https://www.ncbi.nlm.nih.gov/pubmed/29358286 http://dx.doi.org/10.1136/annrheumdis-2017-212401 |
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