Linked Life Data

17483096

Source:http://linkedlifedata.com/resource/pubmed/id/17483096

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2007-6-4
pubmed:abstractText
Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/2'-deoxycytidine 5'-triphosphate, http://linkedlifedata.com/resource/pubmed/chemical/C10ORF2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/DNA, Mitochondrial, http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases, http://linkedlifedata.com/resource/pubmed/chemical/DNA-Directed DNA Polymerase, http://linkedlifedata.com/resource/pubmed/chemical/Deoxycytosine Nucleotides, http://linkedlifedata.com/resource/pubmed/chemical/Deoxyribonucleotides, http://linkedlifedata.com/resource/pubmed/chemical/POLG protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Phosphorus Radioisotopes, http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Kinase, http://linkedlifedata.com/resource/pubmed/chemical/Thymine Nucleotides, http://linkedlifedata.com/resource/pubmed/chemical/thymidine 5'-triphosphate, http://linkedlifedata.com/resource/pubmed/chemical/thymidine kinase 2
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0964-6906
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1400-11
pubmed:dateRevised
2010-6-2
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.
pubmed:affiliation
Mitochondrial Genetics Group, Nuffield Department of Obstetrics and Gynaecology, Level 3, Women's Centre,The John Radcliffe Hospital, Oxford OX3 9DU, UK.
pubmed:publicationType
Journal Article