MELAS ASSOCIATED WITH MUTATIONS IN THE
            <i>POLG1</i>
            GENE

Deschauer, Marcus; Tennant, Stephen; Rokicka, A; He, Langping; Kraya, Torsten; Turnbull, Douglass M.; Zierz, Stephan; Taylor, RW

doi:10.1212/01.wnl.0000261929.92478.3e

Cited by 85 publications

(60 citation statements)

References 6 publications

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“…These strokes are seen mostly in association with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, which is caused by mtDNA mutations. However, some nuclear gene mutations, such as POLG have been associated with a mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes-like presentation [88]. Neuroimaging shows a mixture of cytotoxic and vasogenic edema [89].…”

Section: Stroke-like Lesions In Nonvascular Distributionmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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Section: Stroke-like Lesions In Nonvascular Distributionmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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“…Although the recessive mode of inheritance implies that the mutant proteins are non-competitive at the replication fork, these mutations appear to be more complex than simple loss of function mutations that predispose heterozygous individuals to mitochondrial disorders, because the clinical phenotype is not entirely controlled by the other allele. For example, A467T POLG in trans with R627Q POLG can result in ataxia-neuropathy (37), whereas compound heterozygotes bearing G848S POLG in trans with R627Q POLG can present with MELAS (38). Does the residual DNA polymerase activity of A467T pol ␥ contribute to a milder phenotype?…”

Section: Gly-848 and Arg-852 Are Located At The Face Of The Thumbmentioning

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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“…Including the above two cases, we found 22 reported cases of POLG1 mutations associated with stroke and stroke-like symptoms in the literature (Table 1) (Blok et al 2009;Deschauer et al 2007;Horvath et al 2006;Kollberg et al 2006;Wong et al 2008). Five of these 22 patients were clinically characterized to have AtaxiaNeuropathy Spectrum phenotype, 13 had a phenotype consistent with Alpers, and four patients were unclassified.…”

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confidence: 99%

“…Of the cases where the localization of the stroke was noted, 7/13 were located in the occipital region (Blok et al 2009;Deschauer et al 2007). MRI findings were available in nine patients.…”

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confidence: 99%

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

et al. 2011

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Introduction/Methods Mutations in POLG1, the gene encoding mitochondrial polymerase gamma (Polg), have been associated with a number of well-characterized phenotypes. In this study, we report two cases of patients with biallelic POLG1 mutations and stroke. We also performed a review of the literature and report on all clinical studies of patients with POLG1 mutations in which stroke was described in the phenotype. For each patient, genotype and phenotype are reported.Results Including our two patients, a total of 22 patients have been reported with POLG1 mutations and stroke. The average age of onset of stroke in these patients was 9 years with a range of 1-23 years. In cases where localization was reported, the occipital lobes were the primary location of the infarct. Mutations in the linker-linker or linker-polymerase domains were the most frequent genotype observed. Seizures (16/22) and hepatic dysfunction/failure (8/22) were the most commonly reported symptoms in the stroke cohort.Conclusion This article raises an underrecognized point that patients with POLG1 mutations may suffer a cerebrovascular accident at a young age. The most common location of the infarction is in the occipital lobe. The presentation may be similar to MELAS and can be misdiagnosed as a migrainous stroke.

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MELAS ASSOCIATED WITH MUTATIONS IN THE POLG1 GENE

Cited by 85 publications

References 6 publications

Mitochondrial Disease in Childhood: Nuclear Encoded

Mitochondrial Disease in Childhood: Nuclear Encoded

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

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

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