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: Abdulraheem Almalki, Charlotte L Alston, Alasdair Parker, Ingrid Simonic, Sarju G Mehta, Langping He, Mojgan Reza, Jorge M A Oliveira, Robert N Lightowlers, Robert McFarland, Robert W Taylor, Zofia M A Chrzanowska-Lightowlers
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1842 Issue 1 Pg. 56-64 (Jan 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24161539 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013. Published by Elsevier B.V. All rights reserved.

Chemical References

• RNA, Messenger
• RNA, Transfer
• Cyclooxygenase 1
• Cyclooxygenase 2
• PTGS1 protein, human
• PTGS2 protein, human
• Electron Transport Complex IV
• Amino Acyl-tRNA Synthetases

Topics

• Amino Acid Sequence
• Amino Acyl-tRNA Synthetases (genetics, metabolism)
• Aminoacylation
• Child, Preschool
• Cyclooxygenase 1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Cytochrome-c Oxidase Deficiency (complications, enzymology, genetics, pathology)
• Electron Transport Complex IV (genetics, metabolism)
• Epilepsy (complications, enzymology, genetics, pathology)
• Fibroblasts (cytology, metabolism)
• Gene Expression
• Humans
• Male
• Mitochondria (enzymology, genetics, pathology)
• Molecular Sequence Data
• Muscle, Skeletal (enzymology, pathology)
• Mutation
• Myoblasts (metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Transfer (genetics, metabolism)