We report on a family with spinocerebellar ataxia type 1 (SCA1), in which the age at onset and the severity of the disease do not correlate with the number of CAG repeat units. Although a marked anticipation was observed in the proband, it was not a consequence of an expansion of the CAG tract. None of the expanded alleles contained CAT interruptions. The pathologic expansion in this family was stable during the paternal but not maternal transmission, where it expanded by one trinucleotide and unexpectedly did not lead to anticipation. Our observations suggest that factors other than the length of the CAG repeat play a considerable role in determination of the disease course.
- MeSH
- alely MeSH
- dospělí MeSH
- expanze trinukleotidových repetic MeSH
- fenotyp MeSH
- finanční podpora výzkumu jako téma MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymerázová řetězová reakce MeSH
- rodokmen MeSH
- spinocerebelární ataxie genetika patologie MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
Expansion of CAG trinucleotide repeats has been shown to cause a number of autosomal dominant spinocerebellar ataxias such as SCA1, SCA2, SCA3/MJD, SCA6 and SCA7. These disorders are characterized by a wide inter- and intrafamiliar variation in clinical features. The same mutation can result in different phenotypes and the very similar phenotypes can be caused by different mutations. Therefore it is necessary to investigate more SCA genes (according to prevalence) to identify the causal elongation. We developed a fast and efficient screening method based on touchdown multiplex PCR with fluorescent labelled primers for the most common types of SCAs (SCA 1, 2, 3 and 7). It has been reliable in 113 probands tested. Fragment analysis was performed by using 6% denaturing polyacrylamide gel and employing the automated DNA sequencer. This method considerably shortens the process of molecular genetic screening of SCAs and might be used as a tip for designing other SCA screening sets.
Although spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease is the most common type of SCA worldwide, we did not identify any cases of the disease amongst SCA patients in the Czech population. It has been proposed that the prevalence of large normal alleles correlates with the frequency of various types of SCA. We have therefore attempted to resolve the absence of SCA3 in our population by investigating, within 204 normal chromosomes, the frequency and nature of CAG repeats as well as two intragenic polymorphisms. We found that large normal alleles with more than 33 CAG repeats were observed at a frequency of only 0.49%. Whereas most of the expanded alleles worldwide have the CA haplotype, this was the least common (5.4%) variant observed in our study, although it was associated with a larger mean CAG repeat length (26.9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus.
- MeSH
- alely MeSH
- financování organizované MeSH
- frekvence genu MeSH
- lidé MeSH
- Machado-Josephova nemoc genetika MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- polymorfismus genetický MeSH
- proteiny nervové tkáně genetika MeSH
- spinocerebelární ataxie genetika MeSH
- trinukleotidové repetice MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
