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POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts

POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts
Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human
genetic disease, but demonstrating the functional consequences of de novo mutations remains a major
challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to
ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium
bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy
controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with
compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA
repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair
mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional
consequences of putative pathogenic alleles causing a defect of mtDNA synthesis.
0925-4439
321-325
Stewart, Joanna D
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Schoeler, Susanne
b428bd80-185c-4df4-a078-d6a6fd53c441
Sitarz, Kamil S
3e3c226a-abcd-41ec-b895-6143caabb6d4
Horvath, Rita
e41c9ffa-b0a0-4ebb-a44a-b98a2c6c23cd
Hallmann, Kerstin
c5b36cd2-488f-40a2-8abd-e11a861fae1a
Pyle, Angela
d3062235-0f1b-4ca1-a118-c184f4cb73ca
Yu-Wai-Man, Patrick
2f7cc000-40e1-4733-aded-15291731c83b
Taylor, Robert W
126f6957-333a-4b42-9d09-cc27d27700b8
Samuels, David C
49432a0a-6c63-4ce9-8e35-247f8d54b7f4
Kunz, Wolfram S
fa60f1c1-e2e0-4d2a-bb64-09d02deb98a6
Chinnery, P F
d082fadd-d601-4234-b4b0-ab752db4d443
Stewart, Joanna D
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Schoeler, Susanne
b428bd80-185c-4df4-a078-d6a6fd53c441
Sitarz, Kamil S
3e3c226a-abcd-41ec-b895-6143caabb6d4
Horvath, Rita
e41c9ffa-b0a0-4ebb-a44a-b98a2c6c23cd
Hallmann, Kerstin
c5b36cd2-488f-40a2-8abd-e11a861fae1a
Pyle, Angela
d3062235-0f1b-4ca1-a118-c184f4cb73ca
Yu-Wai-Man, Patrick
2f7cc000-40e1-4733-aded-15291731c83b
Taylor, Robert W
126f6957-333a-4b42-9d09-cc27d27700b8
Samuels, David C
49432a0a-6c63-4ce9-8e35-247f8d54b7f4
Kunz, Wolfram S
fa60f1c1-e2e0-4d2a-bb64-09d02deb98a6
Chinnery, P F
d082fadd-d601-4234-b4b0-ab752db4d443

Stewart, Joanna D, Schoeler, Susanne, Sitarz, Kamil S, Horvath, Rita, Hallmann, Kerstin, Pyle, Angela, Yu-Wai-Man, Patrick, Taylor, Robert W, Samuels, David C, Kunz, Wolfram S and Chinnery, P F (2011) POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1812 (3), 321-325. (doi:10.1016/j.bbadis.2010.11.012). (PMID:21138766)

Record type: Article

Abstract

Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human
genetic disease, but demonstrating the functional consequences of de novo mutations remains a major
challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to
ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium
bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy
controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with
compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA
repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair
mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional
consequences of putative pathogenic alleles causing a defect of mtDNA synthesis.

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Published date: 2011
Organisations: Centre for Biological Sciences

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Local EPrints ID: 355894
URI: http://eprints.soton.ac.uk/id/eprint/355894
ISSN: 0925-4439
PURE UUID: 62a094f4-b372-4255-ac2f-14607175610c
ORCID for Joanna D Stewart: ORCID iD orcid.org/0000-0002-2608-1967

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Date deposited: 04 Sep 2013 16:47
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Joanna D Stewart ORCID iD
Author: Susanne Schoeler
Author: Kamil S Sitarz
Author: Rita Horvath
Author: Kerstin Hallmann
Author: Angela Pyle
Author: Patrick Yu-Wai-Man
Author: Robert W Taylor
Author: David C Samuels
Author: Wolfram S Kunz
Author: P F Chinnery

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