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| Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1 |
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| Author(s): Lafreniere RG, Rochefort DL, Chretien N, Rommens JM, Cochius JI, Kalviainen R, Nousiainen U, Patry G, Farrell K, Soderfeldt B, Federico A, Hale BR, Cossio OH, Sorensen T, Pouliot MA, Kmiec T, Uldall P, Janszky J, Pranzatelli MR, Andermann F, Andermann E, Rouleau GA |
| Source: NATURE GENETICS Volume: 15 Issue: 3 Pages: 298-302 Published: MAR 1997 |
| Times Cited: 107 References: 20 |
| Abstract: Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition(1). Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TCA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families(2). A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable similar to 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences. |
| Document Type: Article |
| Language: English |
| Reprint Address: Lafreniere, RG (reprint author), MCGILL UNIV, CTR RES NEUROSCI, ROOM L12-144, 1650 CEDAR AVE, MONTREAL, PQ H3G 1A4 CANADA |
Addresses:
1. MONTREAL GEN HOSP, RES INST, DEPT NEUROL, MONTREAL, PQ H3G 1A4 CANADA
2. UNIV TORONTO, HOSP SICK CHILDREN, DEPT GENET, TORONTO, ON M5S 1A1 CANADA
3. NORFOLK & NORWICH HOSP, DEPT NEUROL, NORWICH, NORFOLK ENGLAND
4. KUOPIO UNIV HOSP, DEPT NEUROL, SF-70210 KUOPIO, FINLAND
5. UNIV KUOPIO, VAAJASALO HOSP, DEPT CLIN NEUROPHYSIOL, FIN-70211 KUOPIO, FINLAND
6. UNIV LAVAL, DEPT NEUROL, QUEBEC CITY, PQ CANADA
7. UNIV BRITISH COLUMBIA, DEPT PAEDIAT, VANCOUVER, BC V5Z 1M9 CANADA
8. LINKOPING UNIV HOSP, DEPT NEUROL, S-58185 LINKOPING, SWEDEN
9. UNIV SIENA, INST NEUROL SCI, DEPT NEUROL, I-53100 SIENA, ITALY
10. DEPT PEDIAT NEUROL, INDIANAPOLIS, IN USA
11. HOSP SANTA CASA MISERICORDIA, CTR NEUROL & NEUROCIRUGIA, CURITIBA, PARANA BRAZIL
12. UNIV COPENHAGEN, HVIDOVRE HOSP, DEPT NEUROL, DK-2650 HVIDOVRE, DENMARK
13. CHILDRENS MEM HLTH INST, DEPT NEUROL, WARSAW, POLAND
14. DIANALUND EPILEPSY HOSP, CHILD DEPT, DIANALUND, DENMARK
15. ORSZAGOS NEUROL & PSICHIAT INTEZET, DEPT NEUROL, BUDAPEST, HUNGARY
16. GEORGE WASHINGTON UNIV, DEPT NEUROL, WASHINGTON, DC 20052 USA
17. GEORGE WASHINGTON UNIV, DEPT PAEDIAT, WASHINGTON, DC 20052 USA
18. GEORGE WASHINGTON UNIV, DEPT PHARMACOL, WASHINGTON, DC 20052 USA
19. MCGILL UNIV, DEPT NEUROL & NEUROSURG, MONTREAL, PQ H3A 2T5 CANADA
20. MCGILL UNIV, DEPT PEDIAT, MONTREAL, PQ H3A 2T5 CANADA
21. MONTREAL NEUROL HOSP & INST, EPILEPSY SERV, MONTREAL, PQ H3A 2B4 CANADA
22. MCGILL UNIV, DEPT HUMAN GENET, MONTREAL, PQ CANADA
23. MONTREAL NEUROL HOSP & INST, NEUROGENET UNIT, MONTREAL, PQ H3A 2B4 CANADA |
| Publisher: NATURE PUBLISHING CO, 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 |
| Subject Category: Genetics & Heredity |
| IDS Number: WK386 |
| ISSN: 1061-4036 |
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