Lafora's PME is an autosomal recessive fatal disorder characterized by childhood learning disorder or adolescent stimuli sensitive myoclonic seizures, ataxia and progressive neurologic deterioration. In 1995 we mapped the Lafora gene locus in chromosome 6q24. In 1998 we reported mutations in a novel gene (EPM2A) that encodes a protein (laforin) and, in 2000, proved that laforin is actually a dual specificity protein tyrosine phosphatase (ds-PTP), 38 kDa in size and cytoplasmic in location, associated with polyribosomes. Phenotype-genotype correlations and intracellular targeting with two natural mutants in exon 3 or exon 4 found in adolescent onset epilepsy resulted in ubiquitin positive perinuclear aggregates. Intracellular targeting of natural mutants in exon l, found in childhood learning disorders, did not produce the same results. These results suggest that laforin is involved in translational regulation and that protein misfolding and degradation produce adolescent epilepsy phenotypes caused by missense mutations in exon 3 and 4. How missense mutations in exon 1 produce childhood learning disorder need to be explored further. Now we propose to: (l) Continue phenotype-genotype correlations by (a) contrasting mutations in childhood onset learning disorder against adolescent onset epilepsy in new lafora patients; (b) completing sequence of Laforin promotor regions and comparing transcripts of exon 1 versus exons 2, 3 and 4, (c) analyzing intracellular targeting of missense mutations in exon 1 versus exon 3 and 4, (d) producing homozygous null mutants of exon 1 KO mice models and contrasting their phenotypes with homozygous null mutants of exon 4 KO mice models. (2) Use immunocytochemistry and in situ hybridization for studies of development and functions of Laforin in brains of normal mice and humans and mice and humans with Lafora's PME. (3) Search for the second gene (EPM2B) for Lafora's PME. These advances raise our hopes for developing treatment(s) for this fatal epilepsy.
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