Very large numbers of small dendritic LBs in an exceedingly high number of dendrites may play a role in the epileptic diathesis. Genes So far, two genes have been identified as causative of LD, namely EMP2A and EPM2B (also known as NHLRC1) (10, 11). The proportion of LD patients with mutations in one or the other gene varies

according to the population studied. For instance, one Italian study showed that EMP2A is mutated in 22% and EPM2B in 72% of the patients (12). In our families, EPM2A and EMP2B are mutated in 45% and 43%, respectively. Some biopsy proven LD families do not have mutations Inhibitors,research,lifescience,medical in the coding regions of those genes. Linkage and haplotype analysis also excluded linkage to either of the two known genes, suggesting the existence of a third LD locus (13). Genotype-phenotype correlations Genotype-phenotype correlations are a challenge at this point. However, some Inhibitors,research,lifescience,medical studies have suggested that EPM2B patients have a slower disease progression (12, 14). Another correlation was suggested associating mutations in the first exon of EMP2A to an early onset of cognitive deficit (15). EMP2A gene is located on chromosome 6q24. It consists of four exons coding for a 331 amino acid protein called laforin (10). Laforin has two isoforms, A and B which localize to the ER and to the nucleus, respectively (16, 17). The isoforms differ in their C-termini, and mutations in Inhibitors,research,lifescience,medical the unique

isoform A’s C-terminus suggests that this is the disease-relevant isoform (17). To date, 40 different mutations and four polymorphisms were identified in this gene (18). These include missense and nonsense mutations, Epigenetics inhibitor frameshifts and deletions located in the coding region of the gene. Laforin Inhibitors,research,lifescience,medical is a unique

protein in that it contains a carbohydrate-binding domain (CBD) of the CBM20 type (19) in its N-terminus and a dual-specificity protein tyrosine phosphatase (DSP) domain in its C-terminus (6, 20). Given the accumulation of polyglycosans in LD and the presence of a CBD, laforin is thought to play an important role in glycogen metabolism (either its synthesis or degradation) (6). Importantly, Inhibitors,research,lifescience,medical self-dimerization appears to be necessary for laforin to be functional in vivo (21, 22). Co-immunoprecipitation studies suggest that full-length laforin binds an uncharacterized protein termed EMP2AIP1 (for EPM2A interacting protein). This protein does not appear to be responsible for LD in those LD 4-Aminobutyrate aminotransferase families with normal EPM2A and EPM2B genes (23). HIRIP5 is another protein shown to interact with laforin. This protein contains a NifU-like domain and a putative MurD ligase domain. However the role of those domains in HIRIP5 function is not yet clear. Interestingly HIRIP5, like laforin, is ubiquitously expressed in subregions of the brain, but predominantly in the cerebellum and hippocampus. This protein also co-localizes with laforin at the subcellular level.