title: Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.
abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.
authors.affiliation: Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Virtaneva
authors.forename: E
authors.initials: E
authors.lastname: D'Amato
authors.forename: J
authors.initials: J
authors.lastname: Miao
authors.forename: M
authors.initials: M
authors.lastname: Koskiniemi
authors.forename: R
authors.initials: R
authors.lastname: Norio
authors.forename: G
authors.initials: G
authors.lastname: Avanzini
authors.forename: S
authors.initials: S
authors.lastname: Franceschetti
authors.forename: R
authors.initials: R
authors.lastname: Michelucci
authors.forename: C A
authors.initials: CA
authors.lastname: Tassinari
authors.forename: S
authors.initials: S
authors.lastname: Omer
authors.forename: L A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: R M
authors.initials: RM
authors.lastname: Myers
authors.forename: J L
authors.initials: JL
authors.lastname: Dieguez-Lucena
authors.forename: R
authors.initials: R
authors.lastname: Krahe
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: A E
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D055313:Cystatin B; D015891:Cystatins / Q000235:genetics*; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D015183:Restriction Mapping
chemical_list: C524994:CSTB protein, human; D015891:Cystatins; D055313:Cystatin B