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.

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

“…We analyzed the POLG genomic region haplotypes of 17 unrelated patients from Australia or New Zealand (14 from Australia and three from New Zealand), who all carried at least one W748S þ E1143G or A467T allele, as our previously published European samples. 12 The corresponding nucleotide changes are the following (GenBank NM_002693; sequence numbering starts from ATG): c.2243G4C (p.W748S), c.3428A4G (p.E1143G), and c.1399G4A (p.A467T). The other mutations, including the chromosomes carrying the G848S mutation (c.2542G4A), are shown in Figure 1.…”

“…3 -9 We and collaborators have previously reported the W748S mutation as a common cause of ataxia with ancient European origin. 12 The carrier frequency of the W748S mutation was 1:125 in Finland, and the combined frequency of W748S and A467T mutations in the Norwegian population was estimated to be as high as 1:50, 12,14 making it the most common pathogenic POLG mutation. We studied the European W748S disease chromosomes in Finnish, British, Belgian, and Norwegian patients and showed that they all originate from a single common ancient founder.…”

“…We studied the European W748S disease chromosomes in Finnish, British, Belgian, and Norwegian patients and showed that they all originate from a single common ancient founder. 12 In all these patients, we identified a common intragenic single-nucleotide polymorphism (SNP) haplotype and at least remnants of a common haplotype in the immediately adjacent chromosomal region. In addition to European countries, the W748S mutation has been reported in Australia 6 and in one patient with undefined nationality.…”

“…13,15 In our previous haplotype analysis of the European A467T disease chromosomes, a long common haplotype was seen in the British and Belgian patients and remnants of this haplotype were also seen in Norwegian patients, raising the possibility of a common founder also for the A467T mutation. 12 Here, we studied the haplotypes of patients with W748S and A467T mutations from Australia, New Zealand, and the United States to determine whether these mutations would originate from European founders or rather result from recurrent mutation events.…”

Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder

“…POLG1 was downregulated in patients ( Figure 1). POLG1 is one of the causative genes for mitochondrial diseases, such as chronic progressive ophthalmoplegia 35 and mitochondrial recessive ataxia syndrome, 36 both of which frequently comorbid with mood disorders. We showed that transgenic mice with neuron-specific expression of mutant Polg1 displayed BD-like phenotypes.…”