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Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-Translational Function

Lookup NU author(s): Dr Monika Olahova, Dr Charlotte Alston, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 The Authors The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5′-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

Publication metadata

Author(s): Xu Z, Lo W-S, Beck DB, Schuch L, Olahova M, Kopajtich R, Chong YE, Alston CL, Seidl E, Zhai L, Lau C-F, Timchak D, LeDuc CA, Borczuk AC, Teich AF, Juusola J, Sofeso C, Muller C, Pierre G, Hilliard T, Turnpenny PD, Wagner M, Kappler M, Brasch F, Bouffard JP, Nangle LA, Yang X-L, Zhang M, Taylor RW, Prokisch H, Griese M, Chung WK, Schimmel P

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2018

Volume: 103

Issue: 1

Pages: 100-114

Print publication date: 05/07/2018

Online publication date: 05/07/2018

Acceptance date: 12/06/2018

Date deposited: 09/07/2018

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2018.06.006


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust