HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase gamma.

Abstract
The instability of the mitochondrial genome in individuals harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLG) is well recognized, but the underlying molecular mechanisms remain to be elucidated. In 5 pediatric patients with severe myoclonic epilepsy and valproic acid-induced liver failure, we identified 1 novel and 4 previously described pathogenic mutations in the linker region of this enzyme. Although muscle biopsies in these patients showed unremarkable histologic features, postmortem liver tissue available from 1 individual exhibited large cytochrome c oxidase-negative areas. These cytochrome c oxidase-negative areas contained 4-fold less mtDNA than cytochrome c oxidase-positive areas. Decreased copy numbers of mtDNA were observed not only in the liver, skeletal muscle, and brain but also in blood samples from all patients. There were also patient-specific patterns of multiple mtDNA deletions in different tissues, and in 2 patients, there were clonally expanded mtDNA point mutations. The low amount of deleted mtDNA molecules makes it unlikely that the deletions contribute significantly to the general biochemical defect. The clonal expansion of a few individual-specific deletions and point mutations indicates an accelerated segregation of early mtDNA mutations that likely are a consequence of low mtDNA copy numbers. Moreover, these results suggest a potential diagnostic approach for identifying mtDNA depletion in patients.
AuthorsGábor Zsurka, Miriam Baron, Joanna D Stewart, Cornelia Kornblum, Monika Bös, Robert Sassen, Robert W Taylor, Christian E Elger, Patrick F Chinnery, Wolfram S Kunz
JournalJournal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 67 Issue 9 Pg. 857-66 (Sep 2008) ISSN: 0022-3069 [Print] England
PMID18716558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticonvulsants
  • DNA, Mitochondrial
  • Valproic Acid
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human
Topics
  • Adolescent
  • Anticonvulsants (adverse effects)
  • Brain (pathology)
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA Polymerase gamma
  • DNA, Mitochondrial (genetics)
  • DNA-Directed DNA Polymerase (genetics)
  • Diffuse Cerebral Sclerosis of Schilder (genetics, pathology, physiopathology)
  • Epilepsy (genetics)
  • Female
  • Humans
  • Liver (pathology)
  • Liver Failure (chemically induced)
  • Male
  • Muscle, Skeletal (pathology)
  • Mutation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Valproic Acid (adverse effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: