POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts
| Autor: | Patrick Yu-Wai-Man, Wolfram S. Kunz, David C. Samuels, Rita Horvath, Patrick F. Chinnery, Joanna Stewart, Kerstin Hallmann, Susanne Schoeler, Robert W. Taylor, Kamil S. Sitarz, Angela Pyle |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Adult
DNA Replication Male Mitochondrial DNA Heterozygote DNA-Directed DNA Polymerase Mitochondrion Biology Compound heterozygosity DNA Mitochondrial Thymidine Kinase Depletion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Muscular Diseases Ethidium Humans Allele Enzyme Inhibitors Molecular Biology 030304 developmental biology Nucleic Acid Synthesis Inhibitors Genetics 0303 health sciences Ethidium bromide Epilepsy Homozygote DNA replication Infant Heterozygote advantage Diffuse Cerebral Sclerosis of Schilder Fibroblasts Molecular biology DNA Polymerase gamma Mitochondria chemistry Amino Acid Substitution Case-Control Studies Mutation Molecular Medicine Female 030217 neurology & neurosurgery DNA |
| Zdroj: | Biochimica et biophysica acta. 1812(3) |
| ISSN: | 0006-3002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|