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SCA17 repeat expansion: mildly expanded CAG/CAA repeat alleles in neurological disorders and the functional
Chiung-Mei Chen1, Li-Ching Lee, Bing-Wen Soong
1Department of Neurology, Chang Gung Memorial Hospital and Chang-Gung University College of Medicine, Taipei, Taiwan.
Clinica Chimica Acta; International Journal of Clinical Chemistry
|December 17, 2009
Summary
Spinocerebellar ataxia type 17 (SCA17) linked to TATA-box binding protein (TBP) gene mutations was investigated in Taiwanese patients. Mildly expanded alleles were found, and cellular studies revealed altered gene expression and increased cell death.
Area of Science:
- Neurogenetics
- Molecular Neurology
Background:
- Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disorder caused by CAG/CAA repeat expansions in the TATA-box binding protein (TBP) gene.
- The clinical presentation of SCA17 is highly variable.
Purpose of the Study:
- To screen for TBP gene triplet expansions in Taiwanese patients with Parkinson's disease (PD), Alzheimer's disease (AD), and atypical parkinsonism.
- To investigate the functional consequences of expanded TBP alleles using lymphoblastoid cells.
Main Methods:
- Triplet repeat expansion screening in the TBP gene.
- Analysis of gene expression in lymphoblastoid cells derived from patients with expanded alleles.
- Cell viability assays following oxidative stress (TBH treatment).
Main Results:
- Six mildly expanded TBP alleles (44-46 repeats) were identified.
- No significant association was found between expanded alleles and PD, AD, or atypical parkinsonism compared to controls.
- Lymphoblastoid cells with expanded TBP showed reduced expression of HSPA5, HSPA8, and HSPB1, and increased levels of PARK7 protein isoforms.
- Cells with mildly expanded TBP exhibited increased cell death upon tert-butyl hydroperoxide (TBH) treatment.
Conclusions:
- The findings broaden the known clinical spectrum of SCA17.
- Altered gene expression and increased cellular vulnerability to oxidative stress may contribute to SCA17 pathogenesis.
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