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

Stewart JD, Schoeler S, Sitarz KS, Horvath R, Hallmann K, Pyle A, Yu-Wai-Man P, Taylor RW, Samuels DC, Kunz WS, Chinnery PF
Biochim Biophys Acta. 2011 1812 (3): 321-5

PMID: 21138766 · DOI:10.1016/j.bbadis.2010.11.012

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.

Copyright © 2010 Elsevier B.V. All rights reserved.

MeSH Terms (23)

Adult Amino Acid Substitution Case-Control Studies Diffuse Cerebral Sclerosis of Schilder DNA, Mitochondrial DNA-Directed DNA Polymerase DNA Polymerase gamma DNA Replication Enzyme Inhibitors Epilepsy Ethidium Female Fibroblasts Heterozygote Homozygote Humans Infant Male Mitochondria Muscular Diseases Mutation Nucleic Acid Synthesis Inhibitors Thymidine Kinase

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