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

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 heterogeneity3. 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.

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Figure 1: A physical map of the LD critical region at 6q24.
Figure 2: Refined mapping of the gene associated with LD.
Figure 3: Overlapping cDNA clones aligned with genomic DNA sequence.
Figure 4: Nucleotide sequence and predicted amino acid sequence of EPM2A.
Figure 5: Expression pattern of EPM2A.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank J. Rommens, L. Osborne, S. Beck, K. Thorpe, Q. Zhang and the Bloorview Epilepsy Program. Supported by grants from the Hospital for Sick Children (HSC) Foundation and the Medical Research Council of Canada (MRC) to S.W.S. A.J.M. and I.D. are funded by the Wellcome Trust. A.V.D. was supported by NIH grant 5P01-NS21908 (UCLA Comprehensive Epilepsy Program) and contributions from A. Malenfant (Quebec Lafora Society) and V. Faludi (Sweden Lafora effort). S.W.S. is a Scholar of the MRC, L.-C.T. is a Senior Scientist of the MRC and Sellers Chair in Cystic Fibrosis Research at HSC and International Scholar of the Howard Hughes Medical Institute. S.W.S., L.-C.T. and G.R. are members of the Canadian Genetic Disease Network.

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Correspondence to Stephen W. Scherer.

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