Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1

被引:154
作者
Virtaneva, K
DAmato, E
Miao, IM
Koskiniemi, M
Norio, R
Avanzini, G
Franceschetti, S
Michelucci, R
Tassinari, CA
Omer, S
Pennacchio, LA
Myers, RM
DieguezLucena, JL
Krahe, R
delaChapelle, A
Lehesjoki, AE
机构
[1] UNIV HELSINKI, DEPT MED GENET, HAARTMAN INST, FIN-00014 HELSINKI, FINLAND
[2] UNIV HELSINKI, DEPT VIROL, HAARTMAN INST, FIN-00014 HELSINKI, FINLAND
[3] FAMILY FEDERAT FINLAND, DEPT MED GENET, HELSINKI 00100, FINLAND
[4] IST NEUROCHIRURG C BESTA, DEPT NEUROPHYSIOL, I-20133 MILAN, ITALY
[5] UNIV BOLOGNA, BELLARIA HOSP, DEPT NEUROL, I-40139 BOLOGNA, ITALY
[6] KING KHALID HOSP, JEDDAH 21423, SAUDI ARABIA
[7] STANFORD UNIV, DEPT GENET, SCH MED, STANFORD, CA 94305 USA
[8] STANFORD UNIV, DEPT BIOL SCI, STANFORD, CA 94305 USA
[9] UNIV MALAGA, FAC MED, DEPT BIOCHEM & MOL BIOL, MALAGA 29080, SPAIN
关键词
D O I
10.1038/ng0497-393
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(1,2). 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 families(3-5). Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval(7-9), 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(10). 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.
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页码:393 / 396
页数:4
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