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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Almalki, Abdulraheem^1,7  Alston, Charlotte L.¹  Parker, Alasdair²  Simonic, Ingrid³  Mehta, Sarju G.⁴  He, Langping¹  Reza, Mojgan⁵  Oliveira, Jorge M. A.^1,8  Lightowlers, Robert N.⁶  McFarland, Robert¹  Taylor, Robert W.¹  Chrzanowska-Lightowlers, Zofia M. A.¹ 

[1] Newcastle Univ, Inst Ageing & Hlth, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Addenbrookes Hosp, Child Dev Ctr, Cambridge, England

[3] Cambridge Univ Hosp NHS Fdn Trust, Med Genet Labs, Cambridge, England

[4] Addenbrookes Hosp, Dept Med Genet, Cambridge, England

[5] Newcastle Univ, Inst Med Genet, Int Ctr Life, Biobank, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[6] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[7] Taif Univ, Coll Med, At Taif, Saudi Arabia

[8] Univ Porto, Fac Pharm, Dept Drug Sci, REQUIMTE, P-4050313 Oporto, Portugal

关键词: Mitochondria;    Mitochondrial disease;    Aminoacyl-tRNA synthetase;    Aminoacylation;    Mitochondrial translation;    Protein synthesis;   

DOI  :  10.1016/j.bbadis.2013.10.008

来源: Elsevier

【 摘 要 】

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.

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