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Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients: effect of repeat length on the clinical manifestation
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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1998 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 7, no 2, 171-176 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin, We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls, All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset, The repeat length in SCA7 patients ranged from 40 to >200 repeats, The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported, In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with <59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically, The other two SCA7 families could not be traced back to a common ancestor, All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.

Place, publisher, year, edition, pages
1998. Vol. 7, no 2, 171-176 p.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics
URN: urn:nbn:se:umu:diva-3581DOI: 10.1093/hmg/7.2.171ISI: 000071771900003OAI: diva2:142353
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2014-08-29Bibliographically approved
In thesis
1. Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease gene
Open this publication in new window or tab >>Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease gene
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a hereditary neurodegenerative disorder affecting the cerebellum, pons and retina. SCA7 patients present with gait ataxia and visual impairment as the main symptoms. Anticipation, commonly observed in SCA7 families, is a phenomenon where an earlier age at onset and a more severe progression of disease is seen in successive generations.

In order to identify the gene responsible for SCA7, we performed linkage analysis on a Swedish SCA7 kindred. Evidence for linkage of the SCA7 disease locus to a 32 cM region on chromosome 3p12-21.1, between markers D3S1547 and D3S1274, was established.

A number of neurodegenerative disorders associated with anticipation are caused by expanded (CAG)n repeats in their respective disease genes. In order to isolate the SCA7 disease gene we, therefore, screened a human infant brain stem cDNA library for CAG repeat containing clones, mapping to chromosome 3. Four candidate clones were isolated and analysed, but could all be excluded as the SCA7 disease gene.

In 1997, the SCA7 disease gene was identified and, as expected, shown to harbour a CAG repeat, expanded in SCA7 patients. Analysis of the SCA7 CAG repeat region in Swedish SCA7 patients demonstrated that CAG repeat size was negatively correlated to age at onset of disease. Furthermore, patients with larger repeats presented with visual impairment, whereas patients with smaller repeats presented with ataxia as the initial symptom.

SCA7 is the most common autosomal dominant cerebellar ataxia in Sweden and Finland, but rare in other populations. In order to investigate if the relatively high frequency of SCA7 in these countries is the result of a founder effect in the region, a haplotype analysis was performed on all SCA7 families available. All

7 families shared a common haplotype of at least 1.9 cM surrounding the SCA7 locus. In addition, strong linkage disequilibrium was demonstrated for marker D3S1287 closely linked to the SCA7 gene, suggesting a founder effect for the SCA7 mutation in Sweden and Finland.

The function of the SCA7 protein, ataxin-7, is not known and it does not show significant homologies to any previously known proteins. In order to gain insight into the function of ataxin-7 we analysed the expression of ataxin-7 in brain and peripheral tissue from SCA7 patients and controls. In brain, expression was found to be mainly neuronal with a nuclear subcellular localisation. Ataxin-7 expression was found throughout the CNS, not restricted to sites of pathology. We also confirmed previously reported findings of neuronal intranuclear inclusions (NIls) in the brains of SCA7 patients. Based on our findings, we conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression pattern in affected and non-affected tissue or the distribution pattern of aggregated protein.

Place, publisher, year, edition, pages
Umeå: Medicinsk och klinisk genetik, 2000. 68 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 648
Spinocerebellar ataxia, human genetics, linkage analysis, anticipation, CAG repeat expansion, founder effect, protein expression, ATXN7
National Category
Medical Genetics
urn:nbn:se:umu:diva-1900 (URN)91-7191-770-5 (ISBN)
Public defence
2000-05-05, Major Groove, 6L, Institutionen för Mikrobiologi, Umeå Universitet, Umeå, 09:00 (English)
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2010-08-24Bibliographically approved

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