Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy

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Abstract
Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms1,2. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity 3. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies4–8, which suggested LD might be a generalized storage disease6,9. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.