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Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease gene
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 648
Keyword [en]
Spinocerebellar ataxia, human genetics, linkage analysis, anticipation, CAG repeat expansion, founder effect, protein expression, ATXN7
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-1900ISBN: 91-7191-770-5 (print)OAI: oai:DiVA.org:umu-1900DiVA: diva2:142356
Public defence
2000-05-05, Major Groove, 6L, Institutionen för Mikrobiologi, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2010-08-24Bibliographically approved
List of papers
1. Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
Open this publication in new window or tab >>Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
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1995 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 8, 1441-1445 p.Article in journal (Refereed) Published
Abstract [en]

We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation, Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II, Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically, During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11), We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers, Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.

National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-3580 (URN)10.1093/hmg/4.8.1441 (DOI)A1995RM34000027 ()
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2014-08-29Bibliographically approved
2. Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients: effect of repeat length on the clinical manifestation
Open this publication in new window or tab >>Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients: effect of repeat length on the clinical manifestation
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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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics
Identifiers
urn:nbn:se:umu:diva-3581 (URN)10.1093/hmg/7.2.171 (DOI)000071771900003 ()
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2014-08-29Bibliographically approved
3. Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia
Open this publication in new window or tab >>Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia
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2000 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, no 12, 918-922 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCAI gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

Keyword
spinocerebellar ataxia, SCA7, founder effect, haplotype analysis, linkage disequilibrium, Scandinavia
National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-3582 (URN)10.1038/sj.ejhg.5200557 (DOI)000166621600003 ()
Available from: 2000-04-15 Created: 2000-04-15 Last updated: 2014-08-29Bibliographically approved
4. Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
Open this publication in new window or tab >>Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
Show others...
2002 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 1, 29-37 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

Keyword
spinocerebellar ataxia type 7, ataxin-7, expression, subcellular localization
Identifiers
urn:nbn:se:umu:diva-3799 (URN)10.1007/s00401-001-0514-4 (DOI)
Available from: 2004-03-17 Created: 2004-03-17 Last updated: 2010-08-24Bibliographically approved

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