title: Clinical and molecular features of POLG-related mitochondrial disease.
abstract: The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Stumpf
authors.forename: Russell P
authors.initials: RP
authors.lastname: Saneto
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D000074002:DNA Polymerase gamma; D004261:DNA Replication; D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
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