Transcriptional profiling of a mouse model for Lafora disease reveals dysregulation of genes involved in the expression and modification of proteins.

Lafora's progressive myoclonus epilepsy (Lafora disease: LD) is caused by mutations in the EPM2A or NHLRC1 gene, but cellular mechanisms of the pathogenesis remain unclear. In an attempt to understand and elucidate the disease pathway, we have investigated the global gene expression profile in a mouse model for LD that developed a phenotype similar to that observed in human patients, including presence of Lafora bodies, neurodegeneration and profound neurological disturbances. We found 62 differentially expressed genes in the Epm2a knockout mice brains. These genes encode factors involved in protein catabolism, phosphatase, transcription factors, and molecules involved in protein translation, and homeostasis. The two largest functional groups of mRNAs that showed altered expression were predicted to be involved in post-translational modification of proteins and transcriptional regulation, suggesting that defects in protein activity and/or turnover may be the key trigger in the pathophysiology of LD. Furthermore we show that changes in gene expression are not limited to brain and are seen in other organs that develop Lafora bodies. Our study may provide valuable insights into the pathophysiology of LD and may aid in developing potential therapeutic targets.