Human Molecular Genetics Advance Access published online on May 25, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi196
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1 Programme of Neurosciences, Biomedicum-Helsinki, Helsinki University, and Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
* To whom correspondence should be addressed. Defects of mitochondrial polymerase
Received December 12, 2004
Revised May 17, 2005
Accepted May 17, 2005
Article
Functional Defects due to Spacer Region Mutations of Human Mitochondrial DNA Polymerase in a Family with an Ataxia-myopathy Syndrome
2 Graduate Program in Genetics and Department of Biochemistry and Molecular Biology, Michigan State University. East Lansing, MI 48824-1319, USA
3 Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
4 Metabolic Disease Center and Departments of Clinical Chemistry Academic Hospital Schwabing, Munich, Germany
Anu Suomalainen, E-mail: anu.wartiovaara{at}helsinki.fi
Abstract 
(POLG) have been found to 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 two first 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 the three variants, those with R627Q+Q1236H had juvenile-onset ptosis and gait disturbance, whereas 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, binding and processivity of the polymerase. Our biochemical data, the dominant manifestation of A467T and its previously reported high frequency in Belgian population (0.6%) emphasize the role of this mutation as a common cause of neurological disease. Further, we show here biochemical evidence that a polymorphic variant may modify the function of a mutant POLG, if occurring in the same polypeptide. Finally, and surprisingly, other pathogenic spacer mutants showed DNA binding affinities and processivities similar or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations extend beyond the catalytic functions of POLG.
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