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Mutation of the Linker Region of the Polymerase -1 (POLG1) Gene Associated With Progressive External Ophthalmoplegia and Parkinsonism

Gavin Hudson, PhD; Andrew M. Schaefer, PhD, MRCP; Robert W. Taylor, PhD; Watcharee Tiangyou, BSc; Andrew Gibson, PhD, FRCP; Graham Venables, DM, FRCP; Philip Griffiths, MD, FRCOphth; David J. Burn, MD, FRCP; Douglass M. Turnbull, PhD, FRCP; Patrick F. Chinnery, PhD, FRCP

Arch Neurol. 2007;64(4):553-557.

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.

Design  Microsatellite analysis and screening of the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1), and polymerase -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 . 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.

Conclusion  Both autosomal dominant progressive external ophthalmoplegia and parkinsonism can because caused by mutations that directly affect the polymerase domain of polymerase .

Author Affiliations: Mitochondrial Research Group (Drs Hudson, Schaefer, Taylor, Tiangyou, Turnbull, and Chinnery) and Institute of Human Genetics (Dr Chinnery), University of Newcastle upon Tyne, United Kingdom; Departments of Neurology (Drs Schaefer, Burn, Turnbull, and Chinnery) and Ophthalmology (Dr Griffiths), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; and Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom (Drs Gibson and Venables).

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