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Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency

Lookup NU author(s): Abdulraheem Almalki, Dr Charlotte Alston, Dr Mojgan Reza, Professor Robert Lightowlers, Professor Bobby McFarlandORCiD, Professor Robert Taylor, Professor Zofia Chrzanowska-LightowlersORCiD



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


Mitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNAPhe transcript. Functional analysis of the recombinant mutant p.Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNAPhe as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the pAsp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNAPhe. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Almalki A, Alston CL, Parker A, Simonic I, Mehta SG, He LP, Reza M, Oliveira JMA, Lightowlers RN, McFarland R, Taylor RW, Chrzanowska-Lightowlers ZMA

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease

Year: 2014

Volume: 1842

Issue: 1

Pages: 56-64

Print publication date: 01/01/2014

Online publication date: 24/10/2013

Acceptance date: 17/10/2013

Date deposited: 03/09/2014

ISSN (print): 0925-4439

ISSN (electronic):

Publisher: Elsevier


DOI: 10.1016/j.bbadis.2013.10.008


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Funder referenceFunder name
NIHR CSO Healthcare Science Fellowship
Taif University sabbatical scholarship
096919/Z/11/ZWellcome Trust Strategic Award