Clonally expanded mitochondrial DNA mutations in epileptic
individuals with mutated DNA polymerase gamma
Clonally expanded mitochondrial DNA mutations in epileptic
individuals with mutated DNA polymerase gamma
The instability of the mitochondrial genome in individuals
harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase F (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.
857-866
Zsurka, Gabor
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Baron, Miriam
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Stewart, Joanna D.
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Kornblum, Cornelia
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Bos, Monika
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Sassen, Robert
fc628f23-0a4f-4c87-9a3b-1251c532397a
Taylor, Robert W.
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Elger, Christian E.
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Chinnery, Patrick F.
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Kunz, Wolfram
b35a3348-2538-4454-b44f-7b73c59e6727
2008
Zsurka, Gabor
5e68d94a-c627-4d7a-bfc1-a1cd4a2b304d
Baron, Miriam
972f6011-711b-4c32-ba23-78d58ae0defd
Stewart, Joanna D.
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Kornblum, Cornelia
b7b7fee9-2eae-4927-8c96-0b63dc29cbfc
Bos, Monika
73673b93-611c-4f47-8345-7e0852b14505
Sassen, Robert
fc628f23-0a4f-4c87-9a3b-1251c532397a
Taylor, Robert W.
094ef050-e4ce-4394-a68f-35b58255104d
Elger, Christian E.
7ab0a4b4-00a5-4db4-b2dd-8efcb49bf5b9
Chinnery, Patrick F.
a39c5ef7-0cac-401c-a3fb-2e0e2626e6dc
Kunz, Wolfram
b35a3348-2538-4454-b44f-7b73c59e6727
Zsurka, Gabor, Baron, Miriam, Stewart, Joanna D., Kornblum, Cornelia, Bos, Monika, Sassen, Robert, Taylor, Robert W., Elger, Christian E., Chinnery, Patrick F. and Kunz, Wolfram
(2008)
Clonally expanded mitochondrial DNA mutations in epileptic
individuals with mutated DNA polymerase gamma.
Journal of Neuropathology and Experimental Neurology, 67 (9), .
(doi:10.1097/NEN.0b013e3181839b2d).
(PMID:18716558)
Abstract
The instability of the mitochondrial genome in individuals
harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase F (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.
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Published date: 2008
Organisations:
Centre for Biological Sciences
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Local EPrints ID: 355906
URI: http://eprints.soton.ac.uk/id/eprint/355906
ISSN: 0022-3069
PURE UUID: c8ef9b7b-f2a6-4325-b5ab-d00520d40545
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Date deposited: 04 Sep 2013 17:34
Last modified: 14 Mar 2024 14:40
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Author:
Gabor Zsurka
Author:
Miriam Baron
Author:
Joanna D. Stewart
Author:
Cornelia Kornblum
Author:
Monika Bos
Author:
Robert Sassen
Author:
Robert W. Taylor
Author:
Christian E. Elger
Author:
Patrick F. Chinnery
Author:
Wolfram Kunz
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