Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1

Ronald G. Lafrenière, Daniel L. Rochefort, Nathalie Chrétien, Johanna M. Rommens, Jeffrey I. Cochius, Reetta Kälviäinen, Unto Nousiainen, George Patry, Kevin Farrell, Birgitta Söderfeldt, Antonio Federico, Bradford R. Hale, Otto Hernandez Cossio, Troels Sørensen, Marc A. Pouliot, Tomasz Kmiec, Peter Uldall, József Janszky, Michael R. Pranzatelli, Frederick AndermannEva Andermann, Guy A. Rouleau

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150 Citations (Scopus)

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. Recently, two mutations in the cysterin 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, end a C→T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed underactable 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 ~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.

Original languageEnglish
Pages (from-to)298-302
Number of pages5
JournalNature genetics
Volume15
Issue number3
DOIs
Publication statusPublished - Mar 1 1997

ASJC Scopus subject areas

  • Genetics

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    Lafrenière, R. G., Rochefort, D. L., Chrétien, N., Rommens, J. M., Cochius, J. I., Kälviäinen, R., Nousiainen, U., Patry, G., Farrell, K., Söderfeldt, B., Federico, A., Hale, B. R., Cossio, O. H., Sørensen, T., Pouliot, M. A., Kmiec, T., Uldall, P., Janszky, J., Pranzatelli, M. R., ... Rouleau, G. A. (1997). Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature genetics, 15(3), 298-302. https://doi.org/10.1038/ng0397-298