Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene

The progressive myoclonus epilepsy of Lafora type (LD) is an autosomal recessive disorder caused by mutations in the EPM2A gene. We demonstrated recently that EPM2A encodes a dual-specificity phosphatase that is primarily associated with polyribosomes. In the present study, we screened for mutations in the EPM2A gene in 4 Japanese LD families and identified a novel mis-sense mutation, Ala46Pro (136G→C), in heterozygous condition in one patient. In addition, sequence analyses in the patient and control DNA samples identified 4 single nucleotide polymorphisms (SNPs) (75G/A, 120G/T, 159C/G, 171C/T) in the coding region and a novel insertion/deletion polymorphic site (−483[T]_11/10[A]_2/3) and a SNP (−547A/G) in the putative regulatory region of the EPM2A gene. None of the sequence variants, however, co-segregated with the LD phenotype. Haplotype analysis for the 6q24 region in the affected families revealed lack of homozygosity at the EPM2A locus. Our studies suggest that EPM2A is not involved in the disease phenotype of the 4 families studied and that locus heterogeneity for LD may exist in Japanese population also. A simple test described for the detection of Ala46Pro mutation present heterozygously in Japanese population (allele frequency 0.026) can be used for screening this novel allele in a larger sample size