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| Status |
Public on Nov 27, 2012 |
| Title |
Disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The X-chromosomal dystonia parkinsonism syndrome (XDP) is associated with sequence changes within the TAF1/DYT3 multiple transcript system. While most sequence changes are intronic, one, DSC3, is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2-d4. Location of DSC3 in an exon (d4) and utilization of this exon in multiple splice variants suggests an important role of DSC3 in the pathogenesis of XDP. To test this hypothesis we transfected neuroblastoma cells with four expression constructs, including exons d2-d4 (d2-d4/wild-type (wt) and d2-d4/DSC3) and d3-d4 (d3-d4/wt and d3-d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. 362 genes differ between cells containing d2-d4/wt and d2-d4/DSC3. Annotation clustering revealed high enrichment of genes related to dopamine metabolism, vesicular transport, synapse function, Ca++ metabolism, and oxidative stress. 211 genes were differentially expressed in d3-d4/wt vs. d3-d4/DSC3. Annotation clustering highlighted genes in signal transduction and cell-cell interaction. The data shows an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca++ metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3-d4 also affect genes potentially related to neurodegenerative processes their physiologic role as splice variants of TAF1 awaits further exploration.
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| Overall design |
We transfected neuroblastoma cells with four expression constructs, including exons d2-d4 (d2-d4/wild-type (wt) and d2-d4/DSC3) and d3-d4 (d3-d4/wt and d3-d4/DSC3).
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| Contributor(s) |
Herzfeld T, Nolte D, Grznarova M, Hofmann A, Schultze JL, Müller U |
| Citation(s) |
23184149 |
| |
| Submission date |
Sep 26, 2012 |
| Last update date |
Aug 16, 2018 |
| Contact name |
Joachim Schultze |
| E-mail(s) |
[email protected]
|
| Organization name |
LIMES (Life and Medical Sciences Center Genomics and Immunoregulation)
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| Department |
Genomics and Immunoregulation
|
| Street address |
Carl-Troll-Strasse 31
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| City |
Bonn |
| State/province |
NRW |
| ZIP/Postal code |
53115 |
| Country |
Germany |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA175940 |
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