Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin

Abstract

Mutations in the catalytic subunit of the mitochondrial DNA polymerase gamma (POLG) have been found to be an important cause of neurological disease. Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G. Here, we studied the frequency of this allele and found it to be among the most common genetic causes of inherited ataxia in Finland. We identified 27 patients with mitochondrial recessive ataxia syndrome (MIRAS) from 15 Finnish families, with a carrier frequency in the general population of 1 : 125. Since the mutation pair W748S+E1143G has also been described in European patients, we examined the haplotypes of 13 non-Finnish, European patients with the W748S mutation. Haplotype analysis revealed that all the chromosomes carrying these two changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common, northern haplotypes, outside the core haplotype, could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicate that this newly identified ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.

Figure 1

Haplotypes of the Finnish, Norwegian, British, and Belgian patients. Haplotype A and the core haplotype are shown in pink. Haplotypes B and C are shown in blue and yellow, respectively. a, The DNA marker names are written without “D15S.” Proper names can be obtained by placing “D15S” in front of each number shown. b, Four Finnish patients with haplotypes very similar to that of patient D9 are not shown. c, One Norwegian patient with a haplotype very similar to that of patient P3 is not shown.

Figure 2

Birthplaces of the grandparents of the Finnish patients homozygous for the W748S POLG mutation, on a map of Finland. Haplotype A is concentrated in the late-settlement area, whereas haplotypes B and C cluster solely on the western and southern coastlines. The southeastern Karelia belongs presently to Russia and is therefore indicated as separate on the map.