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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:...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
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.
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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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