NDLI: Mitochondrial DNA Polymerase W748S Mutation: A Common Cause of Autosomal Recessive Ataxia with Ancient European Origin

Content Provider	PubMed Central
Author	Hakonen, Anna H. Heiskanen, Silja Juvonen, Vesa Lappalainen, Ilse Luoma, Petri T. Maria, Rantamäki Goethem, Gert Van Löfgren, Ann Hackman, Peter Anders, Paetau Seppo, Kaakkola Kari, Majamaa Teppo, Varilo Udd, Bjarne Helena, Kääriäinen Bindoff, Laurence A. Suomalainen, Anu
Copyright Year	2005
Abstract	Mutations in the catalytic subunit of the mitochondrial DNA polymerase γ (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.
Starting Page	430
File Format	PDF
ISSN	15376605
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	3
Volume Number	77
Language	English
Publisher	The American Society of Human Genetics
Publisher Date	2005-09-01
Access Restriction	Open
Rights Holder	The American Society of Human Genetics
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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