Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F18%3A10375292" target="_blank" >RIV/00216208:11130/18:10375292 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/18:10375292

Result on the web

<a href="https://doi.org/10.1136/annrheumdis-2017-212401" target="_blank" >https://doi.org/10.1136/annrheumdis-2017-212401</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/annrheumdis-2017-212401" target="_blank" >10.1136/annrheumdis-2017-212401</a>

Result language

angličtina

Original language name

Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

Original language 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&apos; 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-) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1 were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients&apos; 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30102 - Immunology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Annals of the Rheumatic Diseases

ISSN

0003-4967

e-ISSN

—

Volume of the periodical

77

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

8

Pages from-to

612-619

UT code for WoS article

000429731800025

EID of the result in the Scopus database

2-s2.0-85044820968