title: 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.
authors.affiliation: Research Program of Neurosciences, Biomedicum-Helsinki, Helsinki, Finland.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Hakonen
authors.forename: Silja
authors.initials: S
authors.lastname: Heiskanen
authors.forename: Vesa
authors.initials: V
authors.lastname: Juvonen
authors.forename: Ilse
authors.initials: I
authors.lastname: Lappalainen
authors.forename: Petri T
authors.initials: PT
authors.lastname: Luoma
authors.forename: Maria
authors.initials: M
authors.lastname: Rantamaki
authors.forename: Gert Van
authors.initials: GV
authors.lastname: Goethem
authors.forename: Ann
authors.initials: A
authors.lastname: Lofgren
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Seppo
authors.initials: S
authors.lastname: Kaakkola
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Teppo
authors.initials: T
authors.lastname: Varilo
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Helena
authors.initials: H
authors.lastname: Kaariainen
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000328:Adult; D001483:Base Sequence; D003001:Cloning, Molecular; D000074002:DNA Polymerase gamma; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005387:Finland / Q000453:epidemiology; D020234:Gait Ataxia / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D005808:Genes, Recessive / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase