Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome
| Autor: | Rita Horváth, Anu Suomalainen, Ningguang Luo, Laurie S. Kaguni, Julia Wanschitz, Stefan Kiechl, Carol L. Farr, Petri Luoma, Wolfgang Löscher |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Mitochondrial DNA Ataxia Molecular Sequence Data Population DNA-Directed DNA Polymerase Biology medicine.disease_cause Human mitochondrial genetics 03 medical and health sciences 0302 clinical medicine Muscular Diseases Genotype Genetics medicine Animals Humans Amino Acid Sequence Allele education Molecular Biology Genetics (clinical) Aged DNA Primers 030304 developmental biology 0303 health sciences Mutation education.field_of_study Base Sequence Sequence Homology Amino Acid Cerebellar ataxia Syndrome General Medicine Middle Aged Mitochondria Pedigree 3. Good health Microscopy Electron Electrophoresis Polyacrylamide Gel Female medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics. 14:1907-1920 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddi196 |
| Popis: | Defects of mitochondrial polymerase gamma (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. |
| Databáze: | OpenAIRE |
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