title: Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism.
abstract: OBJECTIVE
  To define the molecular basis of the autosomal dominant progressive external ophthalmoplegia and parkinsonism in a large family with a dominantly transmitted multiple mitochondrial DNA deletion disorder.
  
  
  METHODS
  Microsatellite analysis and screening of the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1), and polymerase gamma-1 (POLG1) genes.
  
  
  RESULTS
  We identified 3 novel heterozygous POLG1 substitutions in the same family. Autosomal dominant progressive external ophthalmoplegia segregated with 1532G>A in exon 8 and an intronic variant c.2070 + 158G>A in cis. The one patient with parkinsonism had an additional heterozygous substitution in exon 7 in trans (1389G>T). Both coding region mutations were predicted to alter conserved amino acids in the linker region of polymerase gamma. None of the substitutions were found in 192 ethnically matched control chromosomes, 108 patients with progressive external ophthalmoplegia, nor 140 cases of sporadic idiopathic Parkinson disease.
  
  
  CONCLUSIONS
  Both autosomal dominant progressive external ophthalmoplegia and parkinsonism can because caused by mutations that directly affect the polymerase domain of polymerase gamma.
authors.affiliation: Mitochondrial Research Group, University of Newcastle upon Tyne, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Watcharee
authors.initials: W
authors.lastname: Tiangyou
authors.forename: Andrew
authors.initials: A
authors.lastname: Gibson
authors.forename: Graham
authors.initials: G
authors.lastname: Venables
authors.forename: Philip
authors.initials: P
authors.lastname: Griffiths
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005192:Family Health; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000473:pathology*; D020734:Parkinsonian Disorders / Q000473:pathology*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human