Human Molecular Genetics Advance Access originally published online on May 25, 2005
Human Molecular Genetics 2005 14(14):1907-1920; doi:10.1093/hmg/ddi196
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Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome
1Programme of Neurosciences, Biomedicum-Helsinki, Helsinki University, Helsinki, Finland, 2Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland, 3Graduate Program in Genetics and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA, 4Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria and 5Metabolic Disease Center and Department of Clinical Chemistry Academic Hospital Schwabing, Munich, Germany
* To whom correspondence should be addressed at: Programme of Neurosciences, Biomedicum-Helsinki, Room c523B, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. Tel: +358 947171965; Fax: +358 947171964; Email: anu.wartiovaara{at}helsinki.fi
Received April 12, 2005; Accepted May 17, 2005
Defects of mitochondrial polymerase 
(POLG) underlie neurological diseases ranging from myopathies to parkinsonism and infantile Alpers syndrome. The most severe manifestations have been associated with mutations of the ‘spacer’ region of POLG, the function of which has remained unstudied in humans. We identified a family, segregating three POLG amino acid variants, A467T, R627Q and Q1236H. The first two affect the spacer region and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all three variants, those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance and those with a single A467T allele had late-onset ptosis. To evaluate the molecular pathogenesis of these spacer defects, we expressed and purified the mutant proteins and studied their catalytic properties in vitro. The A467T substitution resulted in clearly decreased activity, DNA binding and processivity of the polymerase. Our biochemical data, the dominant manifestation of A467T and its previously reported high frequency in the Belgian population (0.6%), emphasize the role of this mutation as a common cause of neurological disease. Further, biochemical evidence that a polymorphic variant may modify the function of a mutant POLG, if occurring in the same polypeptide, is shown here. Finally, and surprisingly, other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations extend beyond the basic catalytic functions of POLG.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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