DNA polymerase gamma and mitochondrial disease: Understanding the consequence of POLG mutations

Chan, Sherine S.L.; Copeland, William C.

doi:10.1016/j.bbabio.2008.10.007

Cited by 148 publications

(134 citation statements)

References 51 publications

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“…mtDNA deletions are associated with several clinical syndromes, but they also increase with age (Krishnan et al 2007). Mutations in nuclear genes involved in mtDNA replication and maintenance, e.g., POLG1 (NM_001126131.1) encoding the catalytic subunit of mitochondrial DNA polymerase g, can cause accumulation of mtDNA point mutations and deletions throughout life (Chan and Copeland 2009). The most common single large-scale mtDNA deletion is 4,977 base pairs (bp) spanning between the genes for cytochrome B (CytB) and cytochrome c oxidase subunit II (COXII) (Krishnan et al 2007;Remes et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

et al. 2015

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Objective: To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions.Methods: Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

et al. 2015

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“…The human POLG gene is located on 15q24-15q26, spans 23 exons and includes a trinucleotide CAG-repeat region that encodes a polyglutamine stretch near the N-terminus of the mature protein, downstream of the presumed mitochondrial targeting sequence. [5][6][7] It has been reported that human cDNA sequences contain 10 consecutive glutamines encoding CAG codons, followed by a single glutamine encoding a CAA codon and then two further CAG codons. 8 Polyglutamine tracts can be sites for protein-protein interactions; altering the tract in POLG may result in suboptimal or improper mtDNA replication.…”

Section: Introductionmentioning

confidence: 99%

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

Liu¹,

Zhang²,

Haiying³

et al. 2010

Asian J Androl

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Several studies have reported a relationship between the length of the CAG-repeat in the polymerase c (POLG) gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were high (97.38 and 94.13%, respectively), with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile (95.67 and 92.67%, respectively) and fertile men (97.22 and 94.44%, respectively). In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele (pooled odds ratio (OR)50.94; 95% confidence interval (CI): 0.60-1.48). The significance level was not attained with any of the following genetic models: homozygote comparison (not 10/not 10 versus 10/10: OR51.34; 95% CI: 0.66-2.72), heterozygote comparison (10/not 10 versus 10/10: OR51.04; 95% CI: 0.78-1.38), dominant model comparison (not 10/not 10110/ not 10 versus 10/10: OR51.08; 95% CI: 0.79-1.47) and recessive genetic comparison (not 10/not 10 versus 10/not 10110/10: OR51.31; 95% CI: 0.68-2.55). In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.

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“…Alpers syndrome is characterized by refractory seizures, psychomotor regression, and hepatic failure (11,12). Mutation of POLG was first linked to Alpers syndrome in 2004 (13), and to date 45 different point mutations in POLG (18 localized to the polymerase domain) are associated with Alpers syndrome (9,14,15). However, only two Alpers mutations (A467T and W748S, both in the linker region) have been biochemically characterized (16,17).…”

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confidence: 99%

“…mtDNA depletion syndromes are caused by defects in nuclear genes responsible for replication and maintenance of the mitochondrial genome (7). Mutation of POLG, the gene encoding the catalytic subunit of pol ␥, is frequently involved in disorders linked to mutagenesis of mtDNA (8,9). Presently, more than 150 point mutations in POLG are linked with a wide variety of mitochondrial diseases, including the autosomal dominant (ad) and recessive forms of progressive external ophthalmoplegia (PEO), Alpers syndrome, parkinsonism, ataxia-neuropathy syndromes, and male infertility (tools.niehs.nih.gov/polg) (9).…”

mentioning

confidence: 99%

Disease Mutations in the Human Mitochondrial DNA Polymerase Thumb Subdomain Impart Severe Defects in Mitochondrial DNA Replication

Kasiviswanathan

Longley

Chan³

et al. 2009

Journal of Biological Chemistry

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Forty-five different point mutations in POLG, the gene encoding the catalytic subunit of the human mitochondrial DNA polymerase (pol ␥), cause the early onset mitochondrial DNA depletion disorder, Alpers syndrome. Sequence analysis of the C-terminal polymerase region of pol ␥ revealed a cluster of four Alpers mutations at highly conserved residues in the thumb subdomain (G848S, c.2542g3a; T851A, c.2551a3g; R852C, c.2554c3t; R853Q, c.2558g3a) and two Alpers mutations at less conserved positions in the adjacent palm subdomain (Q879H, c.2637g3t and T885S, c.2653a3t). Biochemical characterization of purified, recombinant forms of pol ␥ revealed that Alpers mutations in the thumb subdomain reduced polymerase activity more than 99% relative to the wild-type enzyme, whereas the palm subdomain mutations retained 50 -70% wildtype polymerase activity. All six mutant enzymes retained physical and functional interaction with the pol ␥ accessory subunit (p55), and none of the six mutants exhibited defects in misinsertion fidelity in vitro. However, differential DNA binding by these mutants suggests a possible orientation of the DNA with respect to the polymerase during catalysis. To our knowledge this study represents the first structure-function analysis of the thumb subdomain in pol ␥ and examines the consequences of mitochondrial disease mutations in this region.As the only DNA polymerase found in animal cell mitochondria, DNA polymerase ␥ (pol ␥) 3 bears sole responsibility for DNA synthesis in all replication and repair transactions involving mitochondrial DNA (1, 2). Mammalian cell pol ␥ is a heterotrimeric complex composed of one catalytic subunit of 140 kDa (p140) and two 55-kDa accessory subunits (p55) that form a dimer (3). The catalytic subunit contains an N-terminal exonuclease domain connected by a linker region to a C-terminal polymerase domain. Whereas the exonuclease domain contains essential motifs I, II, and III for its activity, the polymerase domain comprising the thumb, palm, and finger subdomains contains motifs A, B, and C that are crucial for polymerase activity. The catalytic subunit is a family A DNA polymerase that includes bacterial pol I and T7 DNA polymerase and possesses DNA polymerase, 3Ј 3 5Ј exonuclease, and 5Ј-deoxyribose phosphate lyase activities (for review, see Refs. 1 and 2). The 55-kDa accessory subunit (p55) confers processive DNA synthesis and tight binding of the pol ␥ complex to DNA (4, 5).Depletion of mtDNA as well as the accumulation of deletions and point mutations in mtDNA have been observed in several mitochondrial disorders (for review, see Ref. 6). mtDNA depletion syndromes are caused by defects in nuclear genes responsible for replication and maintenance of the mitochondrial genome (7). Mutation of POLG, the gene encoding the catalytic subunit of pol ␥, is frequently involved in disorders linked to mutagenesis of mtDNA (8, 9). Presently, more than 150 point mutations in POLG are linked with a wide variety of mitochondrial diseases, including the autosomal dominant (ad) and...

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DNA polymerase gamma and mitochondrial disease: Understanding the consequence of POLG mutations

Cited by 148 publications

References 51 publications

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

Disease Mutations in the Human Mitochondrial DNA Polymerase Thumb Subdomain Impart Severe Defects in Mitochondrial DNA Replication

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