Molecular background of progressive myoclonus epilepsy

Abstract

Research on human inherited diseases provides a powerful tool to identify an intrinsically important subset of genes vital to healthy functioning of the organism. Progressive myoclonus epilepsies (PMEs) are a group of rare inherited disorders characterized by the association of epilepsy, myoclonus and progressive neurological deterioration. Significant progress has been made in elucidating the molecular background of PMEs. Here, progress towards understanding the molecular pathogenesis of PMEs is reviewed using the most common single cause of PME, Unverricht-Lundborg disease, as an example. Mutations in the gene encoding cystatin B (CSTB), a cysteine protease inhibitor, are responsible for the primary defect in Unverricht-Lundborg disease. CSTB-deficient mice, produced by targeted disruption of the mouse Cstb gene, display a phenotype similar to the human disease, with progressive ataxia and myoclonic seizures. The mice show neuronal atrophy, apoptosis and gliosis as well as increased expression of apoptosis and glial activation genes. Although significant advances towards understanding the molecular basis of Unverricht-Lundborg disease have been achieved, the physiological function of CSTB and the molecular pathogenesis of the disease remain unknown.

Fig. 1. Schematic overview of the CSTB gene structure, mutations and predicted amino acid sequences of mutant proteins. (A) The 98 amino acid CSTB protein is transcribed from three exons depicted as white boxes, with the corresponding lengths of coding sequences in base pairs. White arrowheads indicate the translation start (ATG) and stop (TGA) sites. Black arrowheads indicate the positions of the two transcription start sites. The positions of the EPM1-associated mutations are shown with arrows. (B) Predicted sequences of CSTB proteins representing EPM1 mutations. The major mutation underlying EPM1, the dodecamer repeat expansion in the promoter region, results in production of reduced amounts of CSTB with normal sequence, shown on top. The del2400TC mutation creates a frameshift with two out-of-frame amino acids before an early stop codon. Of the three mutations affecting exon–intron boundaries, the G1925C mutation has been shown to result in skipping of exon 2 (Bespalova et al., 1997b), with consequent in-frame deletion of 34 amino acids from the polypeptide. The consequences of the other two splice site mutations have not been studied.