Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.
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.
Virtaneva
K
K
Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
D'Amato
E
E
Miao
J
J
Koskiniemi
M
M
Norio
R
R
Avanzini
G
G
Franceschetti
S
S
Michelucci
R
R
Tassinari
C A
CA
Omer
S
S
Pennacchio
L A
LA
Myers
R M
RM
Dieguez-Lucena
J L
JL
Krahe
R
R
de la Chapelle
A
A
Lehesjoki
A E
AE
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
C524994:CSTB protein, human; D015891:Cystatins; D055313:Cystatin B