The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

Abstract

Progressive myoclonus epilepsy 1 (EPM1) or Unverricht-Lundborg disease is a human autosomal recessive neurodegenerative disorder caused by mutations in cystatin B (CSTB). The CSTB gene maps to human chromosome 21 and encodes an inhibitor of lysosomal cysteine proteases. Five point mutations have been found, two of which are seen in numerous unrelated patients. However, the main CSTB mutation in EPM1, even among patients of different ethnic origins, is an expansion of a dodecamer repeat (CCCCGCCCCGCG) in the 5′ flanking area of CSTB. Most normal alleles contain either two or three repeats, while rarer normal alleles that are highly unstable contain between 12 and 17 repeats. Mutant expanded alleles have been reported to contain between 30 and 80 copies and are also highly unstable, particularly via parental transmission. There is no apparent correlation between mutant repeat length and disease phenotype. While the repeat expansion is outside the CSTB transcriptional unit, it results in a marked decrease in CSTB expression, at least in certain cell types in vitro. Cstb homozygous knockout mice show some parallels to the phenotype of human EPM1 including myoclonic seizures, development of ataxia and neuropathological changes associated with cell loss via apoptosis. Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.

Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12

“…Promoter activity, and the influence of repeat length, was detectable in one of three neuroblastoma lines, as well as in primary cortical neurons. This result is opposite to that observed in progressive myoclonus epilepsy type 1, in which expansion of a dodecamer repeat causes disease by reducing transcription . The effect of the SCA12 repeat expansion is similar to that observed in FMR1 , with repeats of an intermediate length (56–200 triplets), which is associated with premature ovarian failure and the fragile X‐associated tremor/ataxia syndrome.…”

“…This result is opposite to that observed in progressive myoclonus epilepsy type 1, in which expansion of a dodecamer repeat causes disease by reducing transcription. [46][47][48] The effect of the SCA12 repeat expansion is similar to that observed in FMR1, with repeats of an intermediate length (56-200 triplets), which is associated with premature ovarian failure and the fragile Xassociated tremor/ataxia syndrome. The mechanism by which these repeat expansion mutations influence promoter function remains to be determined, but presumably involves quantitative or qualitative changes in binding efficiency of transcription factors at the promoter locus.…”

Lafora Progressive Myoclonus Epilepsy: Recent Insights into Cell Degeneration

“…As with all of the genetic progressive myoclonic epilepsies, clinically it is characterized by the triad of stimulussensitive myoclonus, epilepsy and progressive neurologic deterioration, and neurological signs depending on the cause [5]. EPM1 is characterized by severe stimulus-sensitive myoclonus, generalized tonic-clonic seizures, and EEG findings with marked sensitivity to photic stimulation [6] 2-EPM2 (Lafora disease): LD is an autosomal recessive disorder, caused by mutations in one of two known genes, EPM2A and EPM2B. EPM2A codes for the protein laforin, a dual specificity phosphatase (DSP) with a carbohydrate binding domain.…”

Proteinaceous cysteine protease inhibitors

“…EPM1, the autosomal, recessive neurodegenerative disorder, is caused in most cases by dodecamer repeat expansion in the promoter region or rarely by point mutations in the coding region (OMIM 601145) [13]. Unlike other PMEs, EPM1 is not associated with inclusion bodies or mitochondrial defects.…”