A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes

Kurt, Bülent; Jaeken, Jaak; Hove, Johan Van; Lagae, Lieven; Löfgren, A.; Everman, David B.; Jayakar, Parul; Naini, Ali; Wierenga, Klaas J.; Goethem, Gert Van; Copeland, William C.; DiMauro, Salvatore

doi:10.1001/archneurol.2009.332

Cited by 27 publications

(17 citation statements)

References 19 publications

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“…Note that we have excluded S305R from the analysis in Fig. 9D because there is no clear link between the single point mutation and the heritable disease; rather, it appears that other mutations in trans contribute to the observed clinical phenotypes (13,53). Our results imply that the single mutation S305R, heterozygous with wild-type POLG, is unlikely to be significantly detrimental because the wild-type allele sufficiently complements defects in replication.…”

Section: Discussionmentioning

confidence: 88%

Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression

Qian

Kachroo

Yellman

et al. 2014

Journal of Biological Chemistry

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Mutations in the human mitochondrial polymerase (Pol‐γ) are associated with various mitochondrial disorders. To correlate biochemically quantifiable defects resulting from point mutations in Pol‐γ with their physiological consequences, we created ‘humanized’ yeast, replacing the yeast mtDNA polymerase (MIP1) with human Pol‐γ. In spite of differences in the replication and repair mechanism, the human polymerase efficiently complements the yeast mip1 knockouts, suggesting common fundamental mechanisms of replication and conserved interactions between the human polymerase and the yeast helicase. We examined the effects of four disease‐related point mutations (S305R, H932Y, Y951N and Y955C) and an exonuclease‐deficient mutant (D198A/E200A). In haploid cells, each mutant results in mtDNA depletion, increased mutation frequency leading to reductions in mtDNA content and mitochondrial dysfunction. Mutation frequencies measured in vivo equal those measured with purified enzyme in vitro. In heterozygous diploid cells, wild‐type Pol‐γ suppresses mutation‐associated growth defects, but continuous growth eventually leads to aerobic respiration defects, reduced mtDNA content and depolarized mitochondrial membranes. The severity of the Pol‐γ mutant phenotype in heterozygous diploid humanized yeast correlates with the age of disease onset and the severity of symptoms observed in humans. Grant Funding Source: Supported by NIH GM044613

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Section: Discussionmentioning

confidence: 88%

Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression

Qian

Kachroo

Yellman

et al. 2014

Journal of Biological Chemistry

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“…In both patients, we were not able to find a second mutation by sequencing of fragments of POLG gene coding regions, which has also been experienced by other researchers [27–29]. The p.W748S mutation was described for the first time in Finnish adults with autosomal recessive ataxic syndrome [30,31].…”

Section: Discussionmentioning

confidence: 47%

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene

et al. 2011

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SummaryBackgroundPOLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion.Material/MethodsA cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations.ResultsThe p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion).ConclusionsOur results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.

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“…Indeed, the father was shown to be heterozygous for the same change. This finding emphasizes the importance of testing MIRAS mutations even in families showing dominant-like SCA, as the high population frequency of POLG1 mutations may result in several introductions of mutations in apparently non-consanguineous families [13].…”

Section: Discussionmentioning

confidence: 76%

Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia

Palin

Hakonen

Korpela

et al. 2012

Journal of the Neurological Sciences

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A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes

Cited by 27 publications

References 19 publications

Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression

Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene

Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia

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