Molecular background of mitochondrial recessive ataxia syndrome, MIRAS

Abstract

Mutations in proteins affecting mtDNA maintenance have been found recently to be common causes of neurodegeration. We present here a new common inherited ataxia, MIRAS (mitochondrial recessive ataxia syndrome). We found MIRAS to be caused by a mutation (W748S) in the catalytic alpha subunit of the DNA polymerase gamma (POLG). MIRAS patients have heterogenous symptoms, including ataxia and epileptic seizures. The carrier frequency of the recessive mutation in the general population in high: 1:125 in Finland, and 1:100 in Norway, making it the most common inherited ataxia in these countries. We haplotyped the POLG locus in European patients with the W748S mutation, and found that all patients in Finland, UK, Norway and Belgium originate from a single common ancient founder. MIRAS is almost a pure central nervous system disease. As the localization and functions of mtDNA maintenance proteins in the brain are largely unknown, we cloned these proteins from the zebrafish and found them to be highly conserved. Our preliminary data indicate that the neuronal localization of these proteins is conserved in zebrafish, fruit fly, mice and human. To understand the mechanism by which W748S causes such a dramatic disease, we are in the process of determining the effect of the mutation on the catalytic activities of POLG. This research was supported by funding from Sigrid Juselius Foundation and University of Helsinki.