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Agnès Rötig - One of the best experts on this subject based on the ideXlab platform.

  • Maternal uniparental disomy of chromosome 2 in a patient with a DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome
    Molecular genetics and metabolism, 2012
    Co-Authors: Coralie Haudry, P. De Lonlay, Arnold Munnich, Valérie Malan, Christine Bole-feysot, Zahra Assouline, Solenn Pruvost, Anaïs Brassier, Jean-paul Bonnefont, Agnès Rötig
    Abstract:

    Abstract We report maternal uniparental disomy of chromosome 2 (matUPD2) in a 9-month-old girl presenting with hepatocerebral mitochondrial DNA depletion syndrome. This patient was homozygous for the c.352C > T (p.Arg118Cys) mutation in DGUOK gene. The proband's mother was heterozygous for the mutation was absent in DNA of the father. For proband, the absence of paternal contribution at the DGUOK locus prompted us to exclude intragenic DGUOK deletion of the paternal allele with Multiplex ligation-dependent probe amplification (MLPA) analysis. We also excluded non-paternity by studying various markers at different loci. Then we performed an analysis of copy number variations and absence of heterozygosity (AOH) on the proband DNA using high resolution oligonucleotides microarray. Several large regions of AOH with no copy number change were detected on chromosome 2 and one of these AOH regions encompassed DGUOK gene. These results were confirmed with haplotype analysis using polymorphic markers. Informative SNPs and microsatellites markers spanning the whole chromosome 2 showed a matUPD2 with heterodisomy and isodisomy regions, the absence of paternal allele and presence of two maternal alleles, with only one maternal allele on the region of DGUOK locus in 2p13.1. This is the first demonstration of matUPD2 with segmental isodisomy at 2p13.1 locus in hepatocerebral mitochondrial DNA depletion syndrome. The identification of UPD2 will impact genetic counseling for the proband's parents. Because the recurrence risk for UPD2 is very low, the risk for disease in further offspring for this couple is negligible.

  • Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1)
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Joanna Poulton, M. Arenas Hernandez, Claude Jardel, Anne Lombès, B. Czermin, Jan-willem Taanman, Michio Hirano, Antonella Spinazzola, Rita Horvath, Agnès Rötig
    Abstract:

    These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database (http://tools.niehs.nih.gov/polg/). We have also excluded mutations in C10orf2 associated with dominant adult onset disorders.

  • The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome
    Molecular genetics and metabolism, 2009
    Co-Authors: N. Brahimi, Valérie Serre, Emmanuelle Sarzi, Marguerite Jambou, Nathalie Boddaert, S. Romano, P. De Lonlay, A. Slama, Arnold Munnich, Agnès Rötig
    Abstract:

    Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.

M T Rodgers - One of the best experts on this subject based on the ideXlab platform.

  • Amino acid-linked platinum(II) compounds: non-canonical nucleoside preferences and influence on glycosidic bond stabilities
    JBIC Journal of Biological Inorganic Chemistry, 2019
    Co-Authors: Bett Kimutai, M T Rodgers, Zhihua Yang, Andrew Roberts, Marcel L. Jones, Xun Bao, Jun Jiang, Christine S. Chow
    Abstract:

    Nucleobases serve as ideal targets where drugs bind and exert their anticancer activities. Cisplatin (cisPt) preferentially coordinates to 2′-deoxyguanosine (dGuo) residues within DNA. The dGuo adducts that are formed alter the DNA structure, contributing to inhibition of function and ultimately cancer cell death. Despite its success as an anticancer drug, cisPt has a number of drawbacks that reduce its efficacy, including repair of adducts and drug resistance. Some approaches to overcome this problem involve development of compounds that coordinate to other purine nucleobases, including those found in RNA. In this work, amino acid-linked platinum(II) (AAPt) compounds of alanine and ornithine (AlaPt and OrnPt, respectively) were studied. Their reactivity preferences for DNA and RNA purine nucleosides (i.e., 2′-deoxyadenosine (dAdo), adenosine (Ado), dGuo, and guanosine (Guo)) were determined. The chosen compounds form predominantly monofunctional adducts by reacting at the N1, N3, or N7 positions of purine nucleobases. In addition, features of AAPt compounds that impact the glycosidic bond stability of Ado residues were explored. The glycosidic bond cleavage is activated differentially for AlaPt-Ado and OrnPt-Ado isomers. Formation of unique adducts at non-canonical residues and subsequent destabilization of the glycosidic bonds are important features that could circumvent platinum-based drug resistance. Graphic abstract

  • gas phase conformations and n glycosidic bond stabilities of sodium cationized 2 deoxyguanosine and guanosine sodium cations preferentially bind to the guanine residue
    Journal of Physical Chemistry B, 2017
    Co-Authors: Y. Zhu, J Oomens, L. A. Hamlow, J. K. Lee, J. Gao, G. Berden, M T Rodgers
    Abstract:

    2′-Deoxyguanosine (dGuo) and guanosine (Guo) are fundamental building blocks of DNA and RNA nucleic acids. In order to understand the effects of sodium cationization on the gas-phase conformations and stabilities of dGuo and Guo, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed. The measured IRMPD spectra of [dGuo+Na]+ and [Guo+Na]+ are compared to calculated IR spectra predicted for the stable low-energy structures computed for these species to determine the most favorable sodium cation binding sites, identify the structures populated in the experiments, and elucidate the influence of the 2′-hydroxyl substituent on the structures and IRMPD spectral features. These results are compared with those from a previous IRMPD study of the protonated guanine nucleosides to elucidate the differences between sodium cationization and protonation on structure. Energy-resolved collision-induced dissociation (ER-CID) experimen...

  • Gas-Phase Conformations and N‑Glycosidic Bond Stabilities of Sodium Cationized 2′-Deoxyguanosine and Guanosine: Sodium Cations Preferentially Bind to the Guanine Residue
    2017
    Co-Authors: Y. Zhu, J Oomens, L. A. Hamlow, J. K. Lee, J. Gao, G. Berden, M T Rodgers
    Abstract:

    2′-Deoxyguanosine (dGuo) and guanosine (Guo) are fundamental building blocks of DNA and RNA nucleic acids. In order to understand the effects of sodium cationization on the gas-phase conformations and stabilities of dGuo and Guo, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed. The measured IRMPD spectra of [dGuo+Na]+ and [Guo+Na]+ are compared to calculated IR spectra predicted for the stable low-energy structures computed for these species to determine the most favorable sodium cation binding sites, identify the structures populated in the experiments, and elucidate the influence of the 2′-hydroxyl substituent on the structures and IRMPD spectral features. These results are compared with those from a previous IRMPD study of the protonated guanine nucleosides to elucidate the differences between sodium cationization and protonation on structure. Energy-resolved collision-induced dissociation (ER-CID) experiments and survival yield analyses of protonated and sodium cationized dGuo and Guo are performed to compare the effects of these cations toward activating the N-glycosidic bonds of these nucleosides. For both [dGuo+Na]+ and [Guo+Na]+, the gas-phase structures populated in the experiments are found to involve bidentate binding of the sodium cation to the O6 and N7 atoms of guanine, forming a 5-membered chelation ring, with guanine found in both anti and syn orientations and C2′-endo (2T3 or 3T2) puckering of the sugar. The ER-CID results, IRMPD yields and the computed C1′–N9 bond lengths indicate that sodium cationization activates the N-glycosidic bond less effectively than protonation for both dGuo and Guo. The 2′-hydroxyl substituent of Guo is found to impact the preferred structures very little except that it enables a 2′OH···3′OH hydrogen bond to be formed, and stabilizes the N-glycosidic bond relative to that of dGuo in both the sodium cationized and protonated complexes

  • mechanisms and energetics for n glycosidic bond cleavage of protonated 2 deoxyguanosine and guanosine
    Physical Chemistry Chemical Physics, 2016
    Co-Authors: Yu Chen, M T Rodgers
    Abstract:

    Experimental and theoretical investigations suggest that hydrolysis of N-glycosidic bonds generally involves a concerted SN2 or a stepwise SN1 mechanism. While theoretical investigations have provided estimates for the intrinsic activation energies associated with N-glycosidic bond cleavage reactions, experimental measurements to validate the theoretical studies remain elusive. Here we report experimental investigations for N-glycosidic bond cleavage of the protonated guanine nucleosides, [dGuo+H]+ and [Guo+H]+, using threshold collision-induced dissociation (TCID) techniques. Two major dissociation pathways involving N-glycosidic bond cleavage, resulting in production of protonated guanine or the elimination of neutral guanine are observed in competition for both [dGuo+H]+ and [Guo+H]+. The detailed mechanistic pathways for the N-glycosidic bond cleavage reactions observed are mapped via electronic structure calculations. Excellent agreement between the measured and B3LYP calculated activation energies and reaction enthalpies for N-glycosidic bond cleavage of [dGuo+H]+ and [Guo+H]+ in the gas phase is found indicating that these dissociation pathways involve stepwise E1 mechanisms in analogy to the SN1 mechanisms that occur in the condensed phase. In contrast, MP2 is found to significantly overestimate the activation energies and slightly overestimate the reaction enthalpies. The 2′-hydroxyl substituent is found to stabilize the N-glycosidic bond such that [Guo+H]+ requires ∼25 kJ mol−1 more than [dGuo+H]+ to activate the glycosidic bond.

Rita Horvath - One of the best experts on this subject based on the ideXlab platform.

  • nucleoside supplementation modulates mitochondrial dna copy number in the DGUOK zebrafish
    Human Molecular Genetics, 2019
    Co-Authors: Rita Horvath, Benjamin Munro, Juliane S Muller
    Abstract:

    Deoxyguanosine kinase (dGK) is an essential rate-limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene encoding deoxyguanosine kinase (DGUOK). Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype. Previous work has shown that in cultured DGUOK patient cells it is possible to rescue mtDNA depletion by increasing substrate amounts for dGK. In this study we developed a mutant DGUOK zebrafish (Danio rerio) line using CRISPR/Cas9 mediated mutagenesis; DGUOK-/- fish have significantly reduced mtDNA levels compared with wild-type (wt) fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wt juvenile animals was significantly reduced, contrasting with previous cell culture studies, possibly because of nucleotide pool imbalance. However, in adult DGUOK-/- fish we detected a significant increase in liver mtDNA copy number when supplemented with both purine nucleosides. This study further supports the idea that nucleoside supplementation has a potential therapeutic benefit in mtDNA depletion syndromes by substrate enhancement of the purine nucleoside salvage pathway and might improve the liver pathology in patients.

  • Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1)
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Joanna Poulton, M. Arenas Hernandez, Claude Jardel, Anne Lombès, B. Czermin, Jan-willem Taanman, Michio Hirano, Antonella Spinazzola, Rita Horvath, Agnès Rötig
    Abstract:

    These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database (http://tools.niehs.nih.gov/polg/). We have also excluded mutations in C10orf2 associated with dominant adult onset disorders.

  • supplementation studies with damp dgmp in primary cultures of human myoblasts and myotubes of patients with mitochondrial dna depletion caused by mutations in the DGUOK and polg1 genes
    Klinische Neurophysiologie, 2009
    Co-Authors: Stefanie Bulst, Hanns Lochmüller, Angela Abicht, Rita Horvath
    Abstract:

    Mitochondrial DNA depletion syndrome (MDS), a frequent cause of severe childhood (hepato)encephalomyopathies, is defined as a reduction of mitochondrial DNA copy number related to nuclear DNA in different tissues which leads to insufficient synthesis of respiratory chain complexes. MDS is responsible for approximately 30–40% of combined RC deficiencies in children. Mutations of eight nuclear genes (DGUOK, POLG1, MVP17. ECGF1, TK2, SUCLA2, SUCLG1 and RRM2B), all involved in the synthesis or maintenance of mitochondrial nucleotide pools, were identified in approximately 40% of all MDS cases implying further genetic heterogeneity. It was previously shown that mtDNA depletion can be prevented by dGMP and dAMP supplementation in culture of deoxyguanosine kinase-deficient fibroblasts. Since then, similar experiments were not published. We performed experiments on human primary myoblasts of patients carrying pathogenic mutations in DGUOK and POLG1. After supplementation with dGMP and dAMP alone and in combination, mtDNA copy number and biochemical analysis of the cytochrome c oxidase (COX) were tested. Serum deprivation and myotube formation triggered a decrease in the mtDNA copy number in primary myotubes of patients carrying pathogenic mutations in DGUOK or POLG1. MtDNA copy number decreased significantly in myotubes of patients with both gene defects but not in controls. Supplementation of the cell culture medium with dGMP and dAMP alone and in combinations rescued the mtDNA depletion in DGUOK deficient cells, but not in myotubes carrying compound heterozygous mutations in POLG1. The effect of the administration of dGMP and dAMP were significant and reproducable. Our results show that supplementation with dGMP/dAMP can increase mtDNA copy number in DGUOK deficient myotubes. The lack of an improvement of mtDNA depletion in POLG1 deficiency reflects a heterogeneous pathomechanism of mtDNA depletion. No adverse effect was observed on high dose supplementation. Further studies are needed to decide about the possible therapeutic implications of dAMP/dGMP supplementation in DGUOK deficiency.

Ian A. Blair - One of the best experts on this subject based on the ideXlab platform.

  • 8 oxo 2 deoxyguanosine as a biomarker of tobacco smoking induced oxidative stress
    Free Radical Biology and Medicine, 2012
    Co-Authors: Clementina Mesaros, Jasbir S. Arora, Ashley Wholer, Anil Vachani, Ian A. Blair
    Abstract:

    Abstract 7,8-Dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dGuo) is a useful biomarker of oxidative stress. However, its analysis can be challenging because 8-oxo-dGuo must be quantified in the presence of dGuo, without artifactual conversion to 8-oxo-dGuo. Urine is the ideal biological fluid for population studies, because it can be obtained noninvasively and it is less likely that artifactual oxidation of dGuo can occur because of the relatively low amounts that are present compared with hydrolyzed DNA. Stable isotope dilution liquid chromatography–selected reaction monitoring/mass spectrometry (LC-SRM/MS) with 8-oxo-[ 15 N 5 ]dGuo as internal standard provided the highest possible specificity for 8-oxo-dGuo analysis. Furthermore, artifact formation was determined by addition of [ 13 C 10 15 N 5 ]dGuo and monitoring of its conversion to 8-oxo-[ 13 C 10 15 N 5 ]dGuo during the analytical procedure. 8-Oxo-dGuo concentrations were normalized for interindividual differences in urine flow by analysis of creatinine using stable isotope dilution LC–SRM/MS. A significant increase in urinary 8-oxo-dGuo was observed in tobacco smokers compared with nonsmokers either using simple urinary concentrations or after normalization for creatinine excretion. The mean levels of 8-oxo-dGuo were 1.65 ng/ml and the levels normalized to creatinine were 1.72 μg/g creatinine. Therefore, stable isotope dilution LC–SRM/MS analysis of urinary 8-oxo-dGuo complements urinary isoprostane (isoP) analysis for assessing tobacco-smoking-induced oxidative stress. This method will be particularly useful for studies that employ polyunsaturated fatty acids, in which a reduction in arachidonic acid precursor could confound isoP measurements.

  • analysis of 7 8 dihydro 8 oxo 2 deoxyguanosine in cellular dna during oxidative stress
    Chemical Research in Toxicology, 2009
    Co-Authors: Dipti Mangal, Seon Hwa Lee, Daljit Vudathala, Jongheum Park, T M Penning, Ian A. Blair
    Abstract:

    Analysis of cellular 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dGuo) as a biomarker of oxidative DNA damage has been fraught with numerous methodological problems. This is primarily due to artifactual oxidation of dGuo that occurs during DNA isolation and hydrolysis. Therefore, it has become necessary to rely on using the comet assay, which is not necessarily specific for 8-oxo-dGuo. A highly specific and sensitive method based on immunoaffinity purification and stable isotope dilution liquid chromatography (LC)-multiple reaction monitoring (MRM)/mass spectrometry (MS) that avoids artifact formation has now been developed. Cellular DNA was isolated using cold DNAzol (a proprietary product that contains guanidine thiocyanate) instead of chaotropic- or phenol-based methodology. Chelex-treated buffers were used to prevent Fenton chemistry-mediated generation of reactive oxygen species (ROS) and artifactual oxidation of DNA bases. Deferoxamine was also added to all buffers in order to complex any residual tr...

  • evidence for the aldo keto reductase pathway of polycyclic aromatic trans dihydrodiol activation in human lung a549 cells
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Jongheum Park, Ian A. Blair, Dipti Mangal, Ronald G Harvey, Kirk A Tacka, Amy M Quinn, T M Penning
    Abstract:

    Polycyclic aromatic hydrocarbons (PAHs) are tobacco carcinogens implicated in the causation of human lung cancer. Metabolic activation is a key prerequisite for PAHs to cause their deleterious effects. Using human lung adenocarcinoma (A549) cells, we provide evidence for the metabolic activation of (±)-trans-7,8dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-trans-dihydrodiol) by aldo-keto reductases (AKRs) to yield benzo[a]pyrene-7,8-dione (B[a]P-7,8-dione), a redox-active o-quinone. We show that B[a]P-7,8-trans-dihydrodiol (AKR substrate) and B[a]P-7,8-dione (AKR product) lead to the production of intracellular reactive oxygen species (ROS) (measured as an increase in dichlorofluorescin diacetate fluores-cence) and that similar changes were not observed with the regioisomer (±)-trans-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene or the diol-epoxide, (±)-anti-7,8-dihydroxy-9α,10β-epoxy-7,8,9,10-tetrahydro-B[a]P. B[a]P-7,8-trans-dihydrodiol and B[a]P-7,8-dione also caused a decrease in glutathione levels and an increase in NADP+/NADPH ratios, with a concomitant increase in single-strand breaks (as measured by the comet assay) and 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dGuo). The specificity of the comet assay was validated by coupling it to human 8-oxo-guanine glycosylase (hOGG1), which excises 8-oxo-Gua to yield single-strand breaks. The levels of 8-oxo-dGuo observed were confirmed by an immunoaffinity purification stable isotope dilution ([15N5]-8-oxo-dGuo) liquid chromatography-electrospray ionization/multiple reaction monitoring/mass spectrometry (LC-ESI/MRM/MS) assay. B[a]P-7,8-trans-dihydrodiol produced DNA strand breaks in the hOGG1-coupled comet assay as well as 8-oxo-dGuo (as measured by LC-ESI/MRM/MS) and was enhanced by a catechol O-methyl transferase (COMT) inhibitor, suggesting that COMT protects against o-quinone-mediated redox cycling. We conclude that activation of PAH-trans-dihydrodiols by AKRs in lung cells leads to ROS-mediated genotoxicity and contributes to lung carcinogenesis.

  • aldo keto reductase and cytochrome p450 dependent formation of benzo a pyrene derived dna adducts in human bronchoalveolar cells
    Chemical Research in Toxicology, 2007
    Co-Authors: Qian Ruan, T M Penning, Stacy L Gelhaus, Ronald G Harvey, Ian A. Blair
    Abstract:

    There is substantial evidence to suggest that polycyclic aromatic hydrocarbons (PAHs) such as benzo-[a]pyrene (B[a]P) induce lung cancer through metabolic activation. As part of a program to delineate the routes of PAH activation, we have examined DNA adducts that are formed in human lung cells. A stable isotope dilution liquid chromatography/multiple reaction monitoring mass spectrometry method was used to quantify eight anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-B[a]P (B[a]PDE)-derived DNA adducts in four H358 human bronchoalveolar cell lines with different phenotypes. In P450 1A1/P450 1B1-induced H358 cells exposed to (±)-B [a]P-7,8-dihydro-7,8-diol (B[a]P-7,8-dihydrodiol), (+)-anti-rrans-B[a]PDE-N 2 -2'-deoxyguanosine [(+)-anti-trans-B[a]PDE-N 2 -dGuo] was the major DNA adduct, and it formed with no lag phase. In AKR1A1-transfected H358 cells, (+)-anti-trans-B[a]PDE-N2-dGuo was also the major adduct with a 3 h lag phase before significant adduct formation was detected. In AKRlA1-transfected H358 cells with induced P450 1A1/P450 1B1, (+)-anti-trans-B[a]PDE-N 2 -dGuo was formed with no lag phase in amounts similar to those in the H358 cells with up-regulated P450 1A1/P450 1B1. Surprisingly, the greatest amount of (+)-anti-trans-B[a]PDE-N 2 -dGuo was formed in the control H358 cells. Furthermore, (+)-anti-trans-B[a]PDE-N 2 -dGuo formation was 2-fold higher in (-)-B[a]P-7,8-dihydrodiol-exposed H358 cells when compared with (±)-B[a]P-7,8-dihydrodiol-exposed cells. The P450 1A1/1B1 inhibitor 2,4,3',5'-tetramethoxystilbene did not attenuate DNA adduct formation in the control H358 cells, suggesting that another P450 was responsible. These data raise the intriguing possibility that P450 1A1/P450 1B1 and AKR1A1 may be protective against (+)-B[a]PDE-mediated DNA damage.

  • dioxododecenoic acid a lipid hydroperoxide derived bifunctional electrophile responsible for etheno dna adduct formation
    Chemical Research in Toxicology, 2005
    Co-Authors: Seon Hwa Lee, Jasbir S. Arora, Maria Victoria Silva Elipe, Ian A. Blair
    Abstract:

    It has been proposed that 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid [13(S)-HPODE]-mediated formation of 4-oxo-2(E)-nonenal and 4-hydroxy-2(E)-nonenal arises from a Hock rearrangement. This suggested that a 4-oxo-2(E)-nonenal-related molecule, 9,12-dioxo-10(E)-dodecenoic acid (DODE), could also result from the intermediate formation of 9-hydroperoxy-12-oxo-10(E)-dodecenoic acid. A recent report has described the formation of DODE-derived etheno adducts when 13(S)-HPODE was allowed to decompose in the presence of 2‘-deoxynucleosides or DNA. However, the regioselectivity of lipid hydroperoxide-derived DODE addition to 2‘-deoxyguanosine (dGuo) or other 2‘-deoxynucleosides was not determined. The structure of carboxynonanone-etheno-dGuo formed from vitamin C-mediated 13(S)-HPODE decomposition has now been established by a combination of 1H and 13C NMR spectroscopy studies of its bis-methylated derivative. The site of dGuo methylation was first established as being at N-5 rather than at O-9 from NMR analysi...

Antonella Spinazzola - One of the best experts on this subject based on the ideXlab platform.

  • Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1)
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Joanna Poulton, M. Arenas Hernandez, Claude Jardel, Anne Lombès, B. Czermin, Jan-willem Taanman, Michio Hirano, Antonella Spinazzola, Rita Horvath, Agnès Rötig
    Abstract:

    These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database (http://tools.niehs.nih.gov/polg/). We have also excluded mutations in C10orf2 associated with dominant adult onset disorders.

  • mpv17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial dna depletion
    Nature Genetics, 2006
    Co-Authors: Antonella Spinazzola, Carlo Viscomi, Erika Fernandezvizarra, Franco Carrara, Pio Dadamo, Sarah E Calvo, Rene Massimiliano Marsano, Claudia Donnini, Hans Weiher
    Abstract:

    The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17−/− mice.