Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions ofEPM2A gene

The progressive myoclonus epilepsy of Lafora type (LD) is an autosomal rece ssive disorder caused by mutations in the EPM2A gene. We demonstrated recen tly that EPM2A encodes a dual-specificity phosphatase that is primarily ass ociated with polyribosomes. In the present study, we screened for mutations in the EPM2A gene in 4 Japanese LID families and identified a novel mis-se nse mutation, Ala46Pro (136G-->C), in heterozygous condition in one patient . In addition, sequence analyses in the patient and control DNA samples ide ntified 4 single nucleotide polymorphisms (SNPs) (75G/A, 120G/T 159C/G, 171 C/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 regi on of the EPM2A gene. None of the sequence variants, however, co-segregated with the LD phenotype. Haplotype analysis for the 6q24 region in the affec ted families revealed lack of homozygosity at the EPM2A locus. Our studies suggest that EPM2A is not involved in the disease phenotype of the 4 famili es studied and that locus heterogeneity for LD may exist in Japanese popula tion also. A simple test described for the detection of Ala46Pro mutation p resent heterozygously in Japanese population (allele frequency 0.026) can b e used for screening this novel allele in a larger sample size. (C) 2001 Ac ademic Press.