Large de novo expansion of CAG repeats in patient with sporadic spinocerebellar ataxia type 7

Bauer, Peter; Kraus, Josef; Maťoška, Václav; Brouckova, Martina; Zumrová, Alena; Goetz, P

doi:10.1007/s00415-004-0482-4

Cited by 13 publications

(5 citation statements)

References 7 publications

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“…We analyzed the SCA1, SCA2, SCA3, SCA6 and SCA7 loci in 118 unrelated Czech probands who were clinically diagnosed as having ADCA or sporadic idiopathic ataxia. We found pathologic CAG expansions at the SCA1 locus in two families, and at the SCA2 locus in 13 families (A Zumrova, PO Bomet, V Matosta, T Marikova, personal communication), whereas the mutation was detected at the SCA7 locus in one patient with sporadic ataxia (Bauer et al. , 2004).…”

Section: Resultsmentioning

confidence: 91%

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Bauer

Zumrová

Maťoška

et al. 2005

Euro J of Neurology

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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.

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Section: Resultsmentioning

confidence: 91%

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Bauer

Zumrová

Maťoška

et al. 2005

Euro J of Neurology

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“…Koide et al excluded meiotic unequal crossover and suggested either a displacement of the 5' end of the Okazaki fragment generating a flap endonuclease FEN1-resistant hairpin or unequal sister chromatid recombination potentially leading to partial intramolecular duplication (11). In SCA2, SCA6, SCA7 and HD, neomutations occur mostly on large normal paternal alleles which undergo the expansion of pure repeats to the pathological range (59)(60)(61)(62)(63)(64)(65)(66). In the two SCA17 de novo cases, expansions also occurred on paternal chromosomes carrying 37 to 39 repeats, although with a different mechanism.…”

Section: Instability and Origin Of The Expansions In The Tbp Genementioning

confidence: 96%

Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4)

2008

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Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington's disease-like phenotype and cerebellar signs. Parkinson's disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down-regulation observed in these diseases.

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“…In some diseases, such as SCA2 and SCA7, the CAG triplets can be extremely unstable. This instability results in either a very long repeat with juvenile age of onset or a de novo pathological expansion from the normal length allele in the absence of an intermediary length repeat (Mao et al 2002;Bauer et al 2004a).…”

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confidence: 99%

The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies

Bauer

Nukina

2009

Journal of Neurochemistry

164

123

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Expansion of CAG trinucleotide repeat within the coding region of several genes results in the production of proteins with expanded polyglutamine (PolyQ) stretch. The expression of these pathogenic proteins leads to PolyQ diseases, such as Huntington’s disease or several types of spinocerebellar ataxias. This family of neurodegenerative disorders is characterized by constant progression of the symptoms and molecularly, by the accumulation of mutant proteins inside neurons causing their dysfunction and eventually death. So far, no effective therapy actually preventing the physical and/or mental decline has been developed. Experimental therapeutic strategies either target the levels or processing of mutant proteins in an attempt to prevent cellular deterioration, or they are aimed at the downstream pathologic effects to reverse or ameliorate the caused damages. Certain pathomechanistic aspects of PolyQ disorders are discussed here. Relevance of disease models and recent knowledge of therapeutic possibilities is reviewed and updated.

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Large de novo expansion of CAG repeats in patient with sporadic spinocerebellar ataxia type 7

Cited by 13 publications

References 7 publications

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4)

The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies

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