Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism.
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.
Hudson
Gavin
G
Mitochondrial Research Group, University of Newcastle upon Tyne, United Kingdom.
Schaefer
Andrew M
AM
Taylor
Robert W
RW
Tiangyou
Watcharee
W
Gibson
Andrew
A
Venables
Graham
G
Griffiths
Philip
P
Burn
David J
DJ
Turnbull
Douglass M
DM
Chinnery
Patrick F
PF
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
D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human