title: Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.
abstract: BACKGROUND
  The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease.
  
  
  RESULTS
  We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids.
  
  
  CONCLUSIONS
  The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
authors.affiliation: Mitochondrial Research Group, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Stewart
authors.forename: S
authors.initials: S
authors.lastname: Tennant
authors.forename: H
authors.initials: H
authors.lastname: Powell
authors.forename: A
authors.initials: A
authors.lastname: Pyle
authors.forename: E L
authors.initials: EL
authors.lastname: Blakely
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: G
authors.initials: G
authors.lastname: Hudson
authors.forename: M
authors.initials: M
authors.lastname: Roberts
authors.forename: D
authors.initials: D
authors.lastname: du Plessis
authors.forename: D
authors.initials: D
authors.lastname: Gow
authors.forename: L D
authors.initials: LD
authors.lastname: Mewasingh
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
authors.forename: S
authors.initials: S
authors.lastname: Omer
authors.forename: A A
authors.initials: AA
authors.lastname: Morris
authors.forename: R
authors.initials: R
authors.lastname: Roxburgh
authors.forename: J H
authors.initials: JH
authors.lastname: Livingston
authors.forename: R
authors.initials: R
authors.lastname: McFarland
authors.forename: D M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: R W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000473:pathology; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000648:ultrastructure; D020125:Mutation, Missense; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics / Q000473:pathology; D016415:Sequence Alignment
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human