title: Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.
abstract: 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-tRNA(Phe) 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-tRNA(Phe) as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the p.Asp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNA(Phe).
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: abdulraheem.almalki@newcastle.ac.uk.
authors.forename: Abdulraheem
authors.initials: A
authors.lastname: Almalki
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Alasdair
authors.initials: A
authors.lastname: Parker
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonic
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Mojgan
authors.initials: M
authors.lastname: Reza
authors.forename: Jorge M A
authors.initials: JM
authors.lastname: Oliveira
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Zofia M A
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics* / Q000378:metabolism; D049148:Aminoacylation; D002675:Child, Preschool; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D030401:Cytochrome-c Oxidase Deficiency / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012343:RNA, Transfer; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D003576:Electron Transport Complex IV; D000604:Amino Acyl-tRNA Synthetases
keywords: Aminoacyl-tRNA synthetase; Aminoacylation; LBSL; MLASA; MRI; Mitochondria; Mitochondrial disease; Mitochondrial translation; OXPHOS; PCH6; Protein synthesis; aaRS; aminoacyl-tRNA synthetase; leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation; magnetic resonance imaging; mitochondrial; mitochondrial DNA; mt-; mtDNA; myopathy, lactic acidosis and sideroblastic anaemia; oxidative phosphorylation; pontocerebellar hypoplasia type 6