The broad long term objective of this research is to find and describe the gene that causes a highly incapacitating hereditary disorder, Progressive Myoclonus Epilepsy of Unverricht and Lundborg, EPM1. It occurs with low frequency worldwide but is particularly common in the Baltic and Mediterranean regions. In the genetically isolated Finnish population it has a high carrier frequency of the order of 1 in 50. Almost nothing is presently known about the pathogenesis of this disorder that afflicts previously health individuals beginning at age 6 to 15. It can be anticipated that once the gene has been described and its protein product characterized it will become possible to determine how the clinical abnormalities arise. In the long term perspective this will be the basis for clarifying the pathogenesis, for improved conventional therapy, prevention, and, eventually, gene therapy. Moreover, understanding the biology of EPM1 may lead to inroads into the mechanisms involved in the pathogenesis of other epilepsies as well. The ultimate goal is to clarify the mechanisms leading not only to hereditary epilepsy syndromes but also to the common epilepsies of sporadic type and unknown etiology. The research group of the principal investigator recently genetically mapped EPM1 to a region in the distal long arm of chromosome 21. Using information on recombinants and by linkage disequilibrium mapping the assignment of EPM1 could be refined to within 1000 kb or less of DNA.
The aim of this project is to clone and characterize EPM1. this will be achieved by preparing a contig map consisting of cosmids and YACs spanning 1000 kb of DNA around the PFKL locus which is one of the loci presently mapping closest to EPM1. Expressed sequences will be sought in the region covered by the contig and genes found will be characterized. To determine which gene is EPM1 mutations will be sought in the DNA of EPM1 patients. Sequencing candidate genes will give information as to their function. Once a gene has been proven to be EPM1, the spectrum of mutations causing EPM1 will be determined and diagnostic procedures based on the detection of mutations devised.
| de la Chapelle, A; Wright, F A (1998) Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci U S A 95:12416-23 |
| Virtaneva, K; Miao, J; Traskelin, A L et al. (1996) Progressive myoclonus epilepsy EPM1 locus maps to a 175-kb interval in distal 21q. Am J Hum Genet 58:1247-53 |
