Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions

Goethem, Gert Van; Dermaut, Bart; Löfgren, A.; Martin, J. J.; Broeckhoven, Christine Van

doi:10.1038/90034

Cited by 725 publications

(493 citation statements)

References 17 publications

Supporting

Mentioning

479

Contrasting

Unclassified

Order By: Relevance

“…Direct sequencing of the complete coding region and the exon/intron boundaries of the candidate genes POLG, 3 POLG2, 4 C10orf2 (Twinkle),5 SLC25A4 (ANT1),7 OPA1, 17 PINK1, 29 and PARK2 30 were carried out as previously described. Large gene deletions or duplications in PARK2 and PINK1 genes were tested by using the MLPA assay for Parkinson disease (SALSA MLPA Kit P051/P052 Parkinson; MRC‐Holland, Amsterdam, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

“…Most of these cases are caused by mutations in nuclear genes directly involved in mtDNA replication and maintenance, that is, POLG 3 and POLG2 ,4 encoding the 2 subunits of mtDNA polymerase, C10orf2 ,5 encoding the mtDNA helicase Twinkle, and DNA2 ,6 encoding an mtDNA helicase/nuclease. Mutations in genes that control the mitochondrial nucleotide pools can also be associated with this phenotype, including SLC25A4 ,7 encoding the heart/muscle‐specific adenine nucleotide translocator ANT1, TYMP ,8 encoding thymidine phosphorylase, TK2 ,9 encoding the mitochondrial thymidine kinase, RRM2B ,10 encoding the p53‐sensitive subunit of ribonucleoside reductase, and DGUOK ,11 encoding mitochondrial deoxyguanosine kinase.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

View full text Add to dashboard Cite

ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

View full text Add to dashboard Cite

show abstract

“…POLG1 was downregulated in patients ( Figure 1). POLG1 is one of the causative genes for mitochondrial diseases, such as chronic progressive ophthalmoplegia 35 and mitochondrial recessive ataxia syndrome, 36 both of which frequently comorbid with mood disorders. We showed that transgenic mice with neuron-specific expression of mutant Polg1 displayed BD-like phenotypes.…”

Section: Biomarkers Of Bipolar Disorder T Kato Et Almentioning

confidence: 99%

Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder

et al. 2011

View full text Add to dashboard Cite

Although there is an urgent need for biological diagnosis of bipolar disorder (BD), there have been no established biomarkers. Gene expression analysis in lymphoblastoid cells (LCLs) would be a promising candidate for biomarkers. In this study, 17 candidate genes were measured in the LCLs of patients with BD. Using the data of the first set of samples (13 patients with bipolar I disorder and 21 controls), three genes, ANK3, RASGRP1 and POLG1, were selected by the logistic regression analysis with a stepwise method. Using the discriminant function generated by this analysis, the first sample was discriminated with the sensitivity of 76% and specificity of 85%. By applying the same function to the second sample set (18 patients with bipolar I and 37 controls), bipolar I disorder could be discriminated from the controls with the sensitivity of 44% and specificity of 81% (v 2 ¼3.97, P¼0.046). This study was the first to suggest a possible role of gene expression analysis of ANK3, RASGRP1 and POLG1 in the LCLs as potential biomarkers of BD.

show abstract

“…Although the specific function of the conserved spacer sequences is not known, a missense mutation in the spacer region of Drosophila pol ␥-␣ causes mitochondrial and nervous system dysfunction and developmental lethality in the larval third instar (24). Furthermore, hereditary progressive external ophthalmoplegia is associated with mutations in human pol ␥-␣, some of which map to the spacer region (5,25,26).Here we examine the consequences of site-directed mutagenesis of conserved amino acid sequences in the spacer region of Drosophila pol ␥-␣. Mutant holoenzymes were expressed from baculovirus constructs in insect cells, purified to near homogeneity, and characterized biochemically.…”

mentioning

confidence: 99%

Mutations in the Spacer Region of Drosophila Mitochondrial DNA Polymerase Affect DNA Binding, Processivity, and the Balance between Pol and Exo Function

Luo

Kaguni

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The catalytic subunit (␣) of mitochondrial DNA polymerase (pol ␥) shares conserved DNA polymerase and 3 -5 exonuclease active site motifs with Escherichia coli DNA polymerase I and bacteriophage T7 DNA polymerase. A major difference between the prokaryotic and mitochondrial proteins is the size and sequence of the region between the exonuclease and DNA polymerase domains, referred to as the spacer in pol ␥-␣. Four ␥-specific conserved sequence elements are located within the spacer region of the catalytic subunit in eukaryotic species from yeast to humans. To elucidate the functional roles of the spacer region, we pursued deletion and site-directed mutagenesis of Drosophila pol ␥. Mutant proteins were expressed from baculovirus constructs in insect cells, purified to near homogeneity, and analyzed biochemically. We find that mutations in three of the four conserved sequence elements within the spacer alter enzyme activity, processivity, and/or DNA binding affinity. In addition, several mutations affect differentially DNA polymerase and exonuclease activity and/or functional interactions with mitochondrial singlestranded DNA-binding protein. Based on these results and crystallographic evidence showing that the templateprimer binds in a cleft between the exonuclease and DNA polymerase domains in family A DNA polymerases, we propose that conserved sequences within the spacer of pol ␥ may position the substrate with respect to the enzyme catalytic domains.The mitochondrion is the eukaryotic organelle that carries out oxidative phosphorylation, fulfilling cellular requirements for energy production. Disruption of mitochondrial energy metabolism can occur by genetic or biochemical mechanisms and is associated with human disorders including degenerative diseases, cancer, and aging (1). Mutations in both the mitochondrial genome and in nuclear genes whose products have mitochondrial functions are linked to mitochondrial disease syndromes. Nuclear genes include those encoding the adenine nucleotide translocator 1 (2), thymidine phosphorylase (3), mitochondrial DNA helicase (Twinkle) (4), and the catalytic subunit of mitochondrial DNA polymerase (pol 1 ␥) (5). Pol ␥ has also been shown to be a target of oxidative damage, which reduces DNA polymerase activity in the mitochondrial matrix (6).Pol ␥ is the only DNA polymerase known to be required for mitochondrial DNA replication in animals (7). It is a member of the family A DNA polymerase group (8, 9), of which Escherichia coli pol I is the prototype (10). The crystal structures of numerous family A DNA polymerases have been solved, revealing a high degree of structural similarity among its members (11)(12)(13)(14)(15)(16)(17). The interaction between DNA polymerase and template-primer DNA has also been revealed in molecular detail by structural determination of pol:DNA co-crystals and in biochemical studies. The pol domain comprises palm, fingers, and thumb subdomains that are separated from the 3Ј-5Ј exonuclease (exo) domain by a cleft that binds the template-primer. Wher...

show abstract

Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions

Cited by 725 publications

References 17 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder

Mutations in the Spacer Region of Drosophila Mitochondrial DNA Polymerase Affect DNA Binding, Processivity, and the Balance between Pol and Exo Function

Contact Info

Product

Resources

About