title: A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits.
abstract: Human mitochondrial DNA (mtDNA) polymerase γ (pol γ) is the sole enzyme required to replicate and maintain the integrity of the mitochondrial genome. It comprises two subunits, a catalytic p140 subunit and a smaller p55 accessory subunit encoded by the POLG2 gene. We describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with adPEO and multiple mtDNA deletions. Biochemical studies of the recombinant mutant p55 protein showed a reduced affinity to the pol γ p140 subunit, leading to impaired processivity of the holoenzyme complex but did not show sensitivity to N-ethylmalaimide (NEM) inhibition, inferring a novel disease mechanism.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Young
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Longley
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D021122:Protein Subunits; D004259:DNA-Directed DNA Polymerase; C544932:POLG2 protein, human