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From the Division of Neurology, Department of Paediatrics (Dr. Minassian), and Bioinformatics Supercomputing Centre (M. Meloche), Department of Genetics (Drs. Minassian, Ianzano, and Scherer), The Hospital for Sick Children, Toronto; The University of Toronto (Drs. Minassian, Ianzano, and Scherer); Neurogenetics Unit, Montreal Neurological Institute (Dr. Andermann), and McGill University (Drs. Andermann and Rouleau), Quebec; Center for Research in Neuroscience (Dr. Rouleau), Montreal General Hospital Research Institute, Canada; and Comprehensive Epilepsy Program (Dr. Delgado-Escueta), Department of Neurology and Brain Research Institute, University of California, Los Angeles School of Medicine, and West Los Angeles DVA Medical Center.
Address correspondence and reprint requests to Dr. S.W. Scherer, Department of Genetics, The Hospital for Sick Children and The University of Toronto, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada; e-mail: steve{at}genet.sickkids.on.ca
BACKGROUND: Lafora’s disease is a progressive myoclonus epilepsy with pathognomonic inclusions (polyglucosan bodies) caused by mutations in the EPM2A gene. EPM2A codes for laforin, a protein with unknown function. Mutations have been reported in the last three of the gene’s exons. To date, the first exon has not been determined conclusively. It has been predicted based on genomic DNA sequence analysis including comparison with the mouse homologue.
OBJECTIVES: 1) To detect new mutations in exon 1 and establish the role of this exon in Lafora’s disease. 2) To generate hypotheses about the biological function of laforin based on bioinformatic analyses.
METHODS: 1) PCR conditions and components were refined to allow amplification and sequencing of the first exon of EPM2A. 2) Extensive bioinformatic analyses of the primary structure of laforin were completed.
RESULTS: 1) Seven new mutations were identified in the putative exon 1. 2) Laforin is predicted not to localize to the cell membrane or any of the organelles. It contains all components of the catalytic active site of the family of dual-specificity phosphatases. It contains a sequence predicted to encode a carbohydrate binding domain (coded by exon 1) and two putative glucohydrolase catalytic sites.
CONCLUSIONS: The identification of mutations in exon 1 of EPM2A establishes its role in the pathogenesis of Lafora’s disease. The presence of potential carbohydrate binding and cleaving domains suggest a role for laforin in the prevention of accumulation of polyglucosans in healthy neurons.
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