A PCR Amplification Method Reveals Instability of the Dodecamer Repeat in Progressive Myoclonus Epilepsy (EPM1) and No Correlation between the Size of the Repeat and Age at Onset
| Autor: | Maria D. Lalioti, Hamish S. Scott, Amel Mrabet, Armand Bottani, T. Chkili, R. Gouider, Sadi Ibrahim, Alain Malafosse, Charlotte Dravet, Stylianos E. Antonarakis, Pierre Genton, Réda Ouazzani, D. Grid, Catherine Buresi |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Polymerase Chain Reaction/methods Adolescent Epilepsies Myoclonic EPM1 Dodecamer-repeat expansion Progressive myoclonus epilepsy Biology Polymerase Chain Reaction Cystatins/ genetics Genetics medicine Humans Genetics(clinical) Cystatin B Age of Onset Allele Child Alleles Genetics (clinical) Repetitive Sequences Nucleic Acid ddc:616 Point mutation Haplotype Epilepsies Myoclonic/ genetics/physiopathology Age at onset medicine.disease Cystatins PCR method Unverricht–Lundborg disease Female Cystatin medicine.symptom Sequence Analysis Myoclonus Research Article |
| Zdroj: | American Journal of Human Genetics, Vol. 62, No 4 (1998) pp. 842-847 |
| ISSN: | 0002-9297 |
| Popis: | Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences. |
| Databáze: | OpenAIRE |
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