Nature Genetics
15, 393 - 396 (1997)
doi:10.1038/ng0497-393
Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1Kimmo Virtaneva1, Elena D'Amato1, Jinmin Miao1, Marjaleena Koskiniemi2, Reijo Norio3, Giuliano Avanzini4, Silvana Franceschetti4, Roberto Michelucci5, Carlo A. Tassinari5, Salah Omer6, 7, Len A. Pennacchio8, 9, Richard M. Myers8, José L. Dieguez-Lucena1, 10, Ralf Krahe1, Albert de la Chapelle1
& Anna-Elina Lehesjoki1, 11
1Department of Medical Genetics, Haartman Institute, University of Helsinki, POBox 21,00014, Helsinki, Finland.
2Department of Virology, Haartman Institute, University of Helsinki, PO Box21,00014, Helsinki, Finland.
3Department of Medical Genetics, The Family Federation of Finland, 00100 Helsinki, Finland.
4Department of Neurophysiology, Istituto Neurologico 'C.Besta', 20133 Milan, Italy.
5Department of Neurology, University of Bologna, Bellaria Hospital, 40139 Bologna, Italy.
6King Khalid Hospital, 21423 Jeddah, Saudi Arabia.
7Present address: Halifax General Hospital, Halifax HX3 OPW, UK.
8Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
9Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
10Department of Biochemistry and Molecular Biology, Málaga University Faculty of Medicine, 29080-Málaga, Spain.
11e-mail: anna-elina.lehesjoki@helsinki.fi. 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 region1,2. 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 families3−5. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval7−9, positional cloning identified the gene encoding cystatin B (C5T6), 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 uncharacterized10. 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.
REFERENCES
- Berkovic, S.F., Berlovic, R., Carpenter, S. & Wolfe, L.S. Progressive myoclonus epilepsies: specific causes and diagnosis. N. Eng. J. Med. 315, 296−305 (1986). | ISI | ChemPort |
- Classification of progressive myoclonus epilepsies and related disorders. Ann. Neurol. 28, 113−116 (1990). | ISI |
- Koskiniemi, M., Donner, M., Majuri, H., Haltia, M. & Norio, R. Progressive myoclonus epilepsy: a clinical and histopathological study. Acta Neurol. Scand. 50, 307−322 (1974). | PubMed | ISI | ChemPort |
- Norio, R. & Koskiniemi, M. Progressive myoclonus epilepsy: genetic and nosological aspects with special reference to 107 Finnish patients. Clin. Genet. 15, 382−398 (1979). | PubMed | ISI | ChemPort |
- Koskiniemi, M., Toivakka, E. & Donner, M. Progressive myoclonus epilepsy. Electroencephalographical findings. Acta Neurol. Scand. 50, 333−359 (1974). | PubMed | ISI | ChemPort |
- Lehesjoki, A.-E. et al. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc. Natl. Acad. Sci. USA 88, 3696−3699 (1991). | PubMed | ChemPort |
- Lehesjoki, A.-E. et al. Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases. Neurology 42, 1545−1550 (1992). | PubMed | ISI | ChemPort |
- Lehesjoki, A.-E. et al. Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping. Hum. Mol. Genet. 2, 1229−1234 (1993). | PubMed | ISI | ChemPort |
- Virtaneva, K. et al. Progressive myoclonus epilepsy EPM1 locus maps to a 175 kb interval in distal 21 q. Am. J. Hum. Genet 58, 1247−1253 (1996). | PubMed | ISI | ChemPort |
- Pennacchio, L.A. et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271, 1731−1734 (1996). | PubMed | ISI | ChemPort |
- Lehesjoki, A.-E. et al. PME of Unverricht-Lundborg type in the Mediterranean region: linkage and linkage disequilibrium confirm the assignment to the EPM1 locus. Hum. Genet. 93, 668−674 (1994). | PubMed | ISI | ChemPort |
- Bell, G.I., Bell, M.J. & Rutter, W.J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295, 31−35 (1982). | PubMed | ISI | ChemPort |
- Owerbach, D. & Gabbay, K.H. Localization of a type I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes 42, 1708−1714 (1993). | PubMed | ISI | ChemPort |
- Bell, G.I., Horita, S. & Karam, J.H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.Diabetes 33, 176−183 (1984). | PubMed | ISI | ChemPort |
- Bennet, S.T. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genet. 9, 284−292 (1995). | Article | PubMed | ISI | ChemPort |
- Kennedy, G.C., German, M.S. & Rutter, W.J. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nature Genet. 9, 293−298 (1995). | Article | PubMed | ISI | ChemPort |
- Lucassen, A.M. et al. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum. Molec. Genet. 4, 501−506 (1995). | PubMed | ISI | ChemPort |
- Gacy, A.M., Goellner, G., Juranic, N., Macura, S. & McMurray, C.T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 81, 533−540 (1995). | Article | PubMed | ISI | ChemPort |
- Chen, X. et al. Hairpins are formed by the single DNA strands of the fragile X triplet repeats: Structure and biological implications. Proc. Natl. Acad. Sci. 92, 5199−5203 (1995). | PubMed | ChemPort |
- Ashley, C.T. Jr. & Warren, S.T. Trinucleotide expansions and human disease. Annu. Rev. Genet. 29, 703−728 (1995). | Article | PubMed | ISI | ChemPort |
- de la Chapelle, A. Disease gene mapping in isolated human populations: the example of Finland. J. Med. Genet. 30, 857−865 (1993). | PubMed | ChemPort |
- Sokal, R.R., Oden, N.L. & Wilson, C. Genetic evidence for the spread of agriculture in Europe by demic diffusion. Nature 9, 143−145 (1991). | Article |
- Cooper, D.N., Krawczak, M. & Antonarakis, S.E. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 259−291 (McGraw-Hill, New York, 1995).
- Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronicGAA triplet repeat expansion. Science 271, 1423−1427 (1996). | PubMed | ISI | ChemPort |
- Warren, S.T. The expanding world of trinucleotide repeats. Science 271, 1374−1375 (1996). | PubMed | ISI | ChemPort |
- Jeffreys, A.J. et al. . Complex gene conversion events in germline mutation at human minisatellites. Nature Genet. 6, 136−145 (1994). | Article | PubMed | ISI | ChemPort |
- Monckton, D.G. et al. Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism. Nature Genet. 8, 162−170 (1994). | Article | PubMed | ISI | ChemPort |
- Stone, N. et al. Construction of a 750 kb bacterial clone contig and restriction map in the region of human chromosome 21 containing the progressive myoclonus epilepsy (EPM1) gene. Genome Res. 6, 218−225 (1996). | PubMed | ISI | ChemPort |
- Kunst, C. & Warren, S. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 77, 853−861 (1994). | Article | PubMed | ISI | ChemPort |
|
