Limits...
Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity.

Callegari S, Gregory PA, Sykes MJ, Bellon J, Andrews S, McKinnon RA, de Barros Lopes MA - PLoS Genet. (2012)

Bottom Line: However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle.Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity.These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

ABSTRACT
Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.

Show MeSH

Related in: MedlinePlus

EF-G2mt protein variants.Alignment of the protein amino acid sequence of the human EF-G2mt protein with the yeast Mef2 protein. Dark shaded areas represent conserved amino acid residues and grey shaded areas represent semi-conserved residues. EF-G2mt SNPs that are semiconserved in yeast MEF2 are shown in italics and fully conserved SNPs are depicted in bold. The five alleles selected for functional characterisation are outlined. The five EF-G2mt protein domains are represented below the alignment. Global alignment of protein sequences was performed using Lalign and the BioEdit sequence alignment editor was used to generate the graphical representation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3375252&req=5

pgen-1002755-g003: EF-G2mt protein variants.Alignment of the protein amino acid sequence of the human EF-G2mt protein with the yeast Mef2 protein. Dark shaded areas represent conserved amino acid residues and grey shaded areas represent semi-conserved residues. EF-G2mt SNPs that are semiconserved in yeast MEF2 are shown in italics and fully conserved SNPs are depicted in bold. The five alleles selected for functional characterisation are outlined. The five EF-G2mt protein domains are represented below the alignment. Global alignment of protein sequences was performed using Lalign and the BioEdit sequence alignment editor was used to generate the graphical representation.

Mentions: A global alignment of the amino acid sequence of the human EF-G2mt protein (Isoform I, AAH15712.1) with the yeast Mef2 protein (CAA59392) reveals 32.1% amino acid sequence identity (Figure 3 and Figure S2). At the commencement of this study, there were nine published non-synonymous Single Nucleotide Polymorphisms (SNPs) in the human EF-G2mt gene, of which five were either conserved or semi-conserved in the yeast MEF2 gene. Three of these variants, EF-G2mtI627T, EF-G2mtE594G and EF-G2mtK334R, are considered rare, with a heterozygosity frequency below one percent. One of the variants, EF-G2mtR744G, has a heterozygosity frequency of three percent and the EF-G2mtR774Q allele has a heterozygosity frequency greater than 20 percent. These five SNPs were selected for functional analysis using the yeast MEF2 gene as a model.


Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity.

Callegari S, Gregory PA, Sykes MJ, Bellon J, Andrews S, McKinnon RA, de Barros Lopes MA - PLoS Genet. (2012)

EF-G2mt protein variants.Alignment of the protein amino acid sequence of the human EF-G2mt protein with the yeast Mef2 protein. Dark shaded areas represent conserved amino acid residues and grey shaded areas represent semi-conserved residues. EF-G2mt SNPs that are semiconserved in yeast MEF2 are shown in italics and fully conserved SNPs are depicted in bold. The five alleles selected for functional characterisation are outlined. The five EF-G2mt protein domains are represented below the alignment. Global alignment of protein sequences was performed using Lalign and the BioEdit sequence alignment editor was used to generate the graphical representation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375252&req=5

pgen-1002755-g003: EF-G2mt protein variants.Alignment of the protein amino acid sequence of the human EF-G2mt protein with the yeast Mef2 protein. Dark shaded areas represent conserved amino acid residues and grey shaded areas represent semi-conserved residues. EF-G2mt SNPs that are semiconserved in yeast MEF2 are shown in italics and fully conserved SNPs are depicted in bold. The five alleles selected for functional characterisation are outlined. The five EF-G2mt protein domains are represented below the alignment. Global alignment of protein sequences was performed using Lalign and the BioEdit sequence alignment editor was used to generate the graphical representation.
Mentions: A global alignment of the amino acid sequence of the human EF-G2mt protein (Isoform I, AAH15712.1) with the yeast Mef2 protein (CAA59392) reveals 32.1% amino acid sequence identity (Figure 3 and Figure S2). At the commencement of this study, there were nine published non-synonymous Single Nucleotide Polymorphisms (SNPs) in the human EF-G2mt gene, of which five were either conserved or semi-conserved in the yeast MEF2 gene. Three of these variants, EF-G2mtI627T, EF-G2mtE594G and EF-G2mtK334R, are considered rare, with a heterozygosity frequency below one percent. One of the variants, EF-G2mtR744G, has a heterozygosity frequency of three percent and the EF-G2mtR774Q allele has a heterozygosity frequency greater than 20 percent. These five SNPs were selected for functional analysis using the yeast MEF2 gene as a model.

Bottom Line: However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle.Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity.These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

ABSTRACT
Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.

Show MeSH
Related in: MedlinePlus