Progressive myoclonus epilepsy type 1 (EPM1), also known as Unverricht-Lundborg disease, is one of the rare forms of epilepsy that shows a clear pattern of autosomal recessive inheritance. The gene defective in this disease was linked to the distal tip of chromosome 21, in band q22.3. In this study, we have collected 93 samples from 15 EPM1 families and 5 affected individuals as the basis for identifying the EPM1 gene. We have also constructed a 770 kb cosmid and bacterial artificial chromosome contig covering the candidate EPM1 region, and have isolated expressed sequences from this contig. For three of the genes that we isolated (GT335, GT334, and PWP2), we have identified and sequenced a full-length cDNA, identified the putative protein, assessed the expression pattern of the gene by Northern blot, determined the exon/intron structure of the gene, characterized basepair polymorphisms within each gene, and finally excluded each of these genes as the one defective in EPM1 patients. Using these new polymorphisms, and others that were available and that we had identified, we were able to construct detailed haplotypes on each of the affected EPM1 chromosomes, to help pinpoint, the location of the EPM1 gene, and help estimate the number of different mutations we might have in our collection. / While these studies were underway, another group identified the cystatin B (STFB) gene as that defective in EPM1. This allowed us to directly test this gene for mutations in our collection of EPM1 patients. We could identify four different mutations in the STFB gene, the most common of which consisted of a variable length insertion in the 5 ' flanking region of the gene, and which was previously undescribed. This mutation, which is found in 78% of unrelated EPM1 chromosomes we studied, showed some level of meiotic instability, and mapped to a polymorphic 12-bp GC-rich repeat. Using a combination of PCR and Southern blotting assays, we could accurately diagnose nearly 100% of all EPM1 patients. This represents a significant step forward in our ability to diagnose this disease at the molecular level, and should allow a more precise definition of the progressive myoclonus epilepsies, as a whole.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.34654 |
| Date | January 1997 |
| Creators | Lafrenière, Ronald G. |
| Contributors | Rouleau, G. A. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001615715, proquestno: NQ36996, Theses scanned by UMI/ProQuest. |
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