The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA

Mandel, Hanna; Szargel, Raymonde; Labay, Valentina; Elpeleg, Orly; Saada, Ann; Shalata, Adel; Anbinder, Yefim; Berkowitz, Drora; Hartman, Corina; Barak, Moshe; Eriksson, Staffan; Cohen, Nadine

doi:10.1038/ng746

Cited by 515 publications

(359 citation statements)

References 28 publications

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“…Patient 1 manifested with a severe progressive metabolic encephalomyopathy and the brain MRI of Patient 1 disclosed white matter degeneration as well as basal ganglia and thalamic lesions resembling Leigh syndrome. Similar encephalopathic phenotypes have been described in MDDS caused by several mtDNA maintenance genes including in SUCLA2 and SUCLG1 (Ostergaard et al 2007a, b;Carrozzo et al 2007;Elpeleg et al 2005), DGUOK (Mandel et al 2001;Dimmock et al 2008) and RRM2B (Bornstein et al 2008;Acham-Roschitz et al 2009;Kollberg et al 2009). Patient 1 was also found with generalized aminoaciduria that has previously been described in MDDS patients (Uusimaa et al 2014).…”

Section: Discussionsupporting

confidence: 70%

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: Discussionsupporting

confidence: 70%

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

et al. 2015

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“…Saada et al [32] have demonstrated that TTP is significantly reduced in fibroblast cells cultured from these patients. Liver damage has not been reported in the few individuals that have been characterized to have a partial thymidine kinase 2 deficiency; however, a similar mitochondrial DNA depletion disease affecting liver and brain has been characterized in which the matrix enzyme deoxyguanosine kinase is deficient [33]. The difference in the presenting pathology of these two disorders is unknown, but it may be related to tissue specific levels of expression of the respective enzymes.…”

Section: Discussionmentioning

confidence: 99%

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Lynx

Bentley

McKee

2006

Biochemical Pharmacology

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Abstract3′-Azido-3′-deoxythymidine (AZT) is a staple of highly active antiretroviral therapy (HAART). Prior to HAART, long-term use of high-dosage AZT caused myopathy, cardiomyopathy, and hepatotoxicity, associated with mitochondrial DNA depletion. As a component of HARRT, AZT causes cytopenias and lipodystrophy. AZT-5′-triphosphate (AZTTP) is a known inhibitor of the mitochondrial polymerase γ and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart mitochondria, AZT phosphorylation beyond AZT-5′-monophosphate (AZTMP) was not detected. Rather, AZT was shown to be a more potent inhibitor of thymidine phosphorylation (50% inhibitory concentration (IC 50 ) of 7.0 ± 1.0 μM) than AZTTP is of polymerase γ (IC 50 of >100 μM), suggesting that depletion of mitochondrial stores of TTP may limit replication. This work has investigated whether an identical mechanism might account for the hepatotoxicity seen with long-term use of AZT. Isolated rat liver mitochondria were incubated with labeled thymidine or AZT, and the rate and extent of phosphorylation were determined by HPLC analysis of acid-soluble extracts of the incubated mitochondria. The results showed that in the phosphorylation of thymidine to TMP, liver mitochondria exhibit a higher V max and K m than heart mitochondria, but otherwise heart and liver mitochondria display similar kinetics. AZT is phosphorylated to AZTMP, but no further phosphorylated forms were detected. In addition, AZT inhibited the production of TTP, with an IC 50 of 14.4 ± 2.6 μM AZT. This is higher, but comparable to, the results seen in isolated rat heart mitochondria. KeywordsAZT; Liver mitochondria; Thymidine; Mitochondrial toxicity; Thymidine kinase 2; Reverse transcriptase inhibitors Abbreviations AIDS, acquired immunodeficiency syndrome; AZT, 3′-azido-3′-deoxythymidine; AZTDP, 3′-azido-3′-deoxythymidine-5′-diphosphate; AZTMP, 3′-azido-3′-deoxythymidine-5′-monophosphate; AZTTP, 3′-azido-3′-deoxythymidine-5′-triphosphate; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; IC 50 , 50% inhibitory concentration; S.E.M., standard error of mean

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“…Autoradiographic observations (35,36) had shown specific labeling of mt DNA from deoxynucleosides, and metabolic experiments claimed depletion of cytosolic but not of mt dTTP after inhibition with amethopterin (37). Support also came from the discovery that in humans genetic deletion of intra-mt deoxynucleoside kinase activity results in depletion of mt DNA (4,5).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Interrelations within Guanine Deoxynucleotide Pools for Mitochondrial and Nuclear DNA Maintenance

Leanza

Ferraro

Reichard

et al. 2008

Journal of Biological Chemistry

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Mitochondrial deoxynucleoside triphosphates are formed and regulated by a network of anabolic and catabolic enzymes present both in mitochondria and the cytosol. Genetic deficiencies for enzymes of the network cause mitochondrial DNA depletion and disease. We investigate by isotope flow experiments the interrelation between mitochondrial and cytosolic deoxynucleotide pools as well as the contributions of the individual enzymes of the network to their maintenance. To study specifically the synthesis of dGTP used for the synthesis of mitochondrial and nuclear DNA, we labeled hamster CHO cells or human fibroblasts with [ 3 H]deoxyguanosine during growth and quiescence and after inhibition with aphidicolin or hydroxyurea. At time intervals we determined the labeling of deoxyguanosine nucleotides and DNA and the turnover of dGTP from its specific radioactivity in the separated mitochondrial and cytosolic pools. In both cycling and quiescent cells, the import of deoxynucleotides formed by cytosolic ribonucleotide reductase accounted for most of the synthesis of mitochondrial dGTP, with minor contributions by cytosolic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. A dynamic isotopic equilibrium arose rapidly from the shuttling of deoxynucleotides between mitochondria and cytosol, incorporation of dGTP into DNA, and degradation of dGMP. Inhibition of DNA synthesis by aphidicolin marginally affected the equilibrium. Inhibition of DNA synthesis by blockage of ribonucleotide reduction with hydroxyurea instead disturbed the equilibrium and led to accumulation of labeled dGTP in the cytosol. The turnover of dGTP decreased, suggesting a close connection between ribonucleotide reduction and pool degradation. Mitochondrial (mt)2 deoxynucleotides are formed and regulated by a network of anabolic and catabolic enzymes located in both the cytosol and mitochondria. The enzymes are of considerable medical interest. Many drugs used in cancer and virus therapy are deoxynucleoside analogs whose activity requires phosphorylation by kinases (1) and whose efficacy and toxicity is affected by the interplay between the enzymes in the network. The enzymes may also be involved in oxidative damage by activating modified bases such as 8-oxoguanine for incorporation into RNA and DNA (2). Moreover, an increasing number of diseases with depletion of mt DNA arise from genetic deficiency of enzymes in the network (3). In some cases the genetic deficiency leads to depletion of mt deoxyribonucleoside triphosphate (dNTP) (4 -6), in other cases to overproduction (7-9). In both instances the disturbed normal balance between the four dNTPs results in disease. Early examples are the catabolic phosphorylases that degrade purine (7) or thymine nucleosides (9). Their loss causes overproduction of dGTP or dTTP, with the affected individuals suffering from immune deficiency (7,8) or mitochondrial neurogastrointestinal encephalomyopathy (9), respectively. Later discovered examples are the anabolic mt salvage enzymes deoxyguanosine kinase (dGK) (4...

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The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA

Cited by 515 publications

References 28 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

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Metabolic Interrelations within Guanine Deoxynucleotide Pools for Mitochondrial and Nuclear DNA Maintenance

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