Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1

Abstract

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.

Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients

“…3,5,7 The expansion has been visualized with Southern hybridization, PCR amplification followed by hybridization or PCR amplification under special conditions with deaminated DNAs as templates. 10,17 -19 Using a new PCR-based protocol to detect the expansion mutation, we were able to correctly determine the genotype previously determined by Southern blotting.…”

“…8,9 Most of the disease alleles harbour an unstable expansion of at least 30 copies of a normally polymorphic 12-nucleotide, dodecamer repeat located in the promoter region of the CSTB gene. 3,5,7,10 Three reported EPM1 mutations affect splice sites (c.67-1G4C, c.168G4A, c.169-2A4G), two result in amino-acid changes (c.10G4C, p.G4R; c.212A4C, p.Q71P) and two predict truncated proteins either through creating a stop codon (c.202C4T) or producing a frameshift (c.218_219delTC).…”

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study

“…The diagnosis of EPM1 was hypothesised on the basis of its typical electroclinical presentation and confirmed by the finding of a dodecamer expansion of the cstb gene (Virtaneva et al 1997). The enrolled patients presented with mildly to moderately severe myoclonus (a score of two or three on a simplified rating scale, Magaudda et al 2004) and were receiving similar anti-epileptic treatment: valproate (10), levetiracetam (3), topiramate (2), benzodiazepine (1), bromazepam (1), clonazepam (1), lamotrigine (1), phenobarbital (1), and piracetam (1).…”

Zinc Regulates the Stability of Repetitive Minisatellite DNA Tracts During Stationary Phase

“…Rare alleles of the minisatellite repeat tract adjacent to the HRAS1 oncogene in humans have been correlated with breast, colon, and urinary tract cancer and acute leukemia (Krontiris et al 1993;Krontiris 1995a,b;Ding et al 1999;Vega et al 2001a,b). Tract changes in minisatellites associated with the cystatin B and IDDM2 genes may be responsible for progressive myoclonus epilepsy and insulin-dependent diabetes mellitus, respectively (Kennedy et al 1995;Lafreniere et al 1997;Virtaneva et al 1997).…”