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

Journal of Neuropathology and Experimental Neurology
G ZsurkaWolfram S Kunz

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-specif...Continue Reading

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Citations

Mar 13, 2010·Intensive Care Medicine·Angela PyleSimon V Baudouin
Aug 29, 2012·Acta Neuropathologica·Stefan VielhaberWolfram S Kunz
Nov 12, 2010·Journal of Bioenergetics and Biomembranes·Gábor Zsurka, Wolfram S Kunz
Feb 1, 2011·Brain : a Journal of Neurology·Mark O Cunningham, Patrick F Chinnery
Aug 1, 2012·Oxidative Medicine and Cellular Longevity·Carlos Clayton Torres AguiarSilvania Maria Mendes Vasconcelos
Oct 12, 2011·Journal of Child Neurology·Richard E Frye
Sep 8, 2017·International Journal of Molecular Sciences·Alexei P KudinWolfram S Kunz
May 21, 2014·Annals of Neurology·Charalampos TzoulisLaurence A Bindoff
Jan 24, 2013·IUBMB Life·Gábor Zsurka, Wolfram S Kunz
Dec 9, 2010·Biochimica Et Biophysica Acta·Joanna D StewartPatrick F Chinnery

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