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Somatic expansion of the (CAG)n repeat in Huntington disease brains
K E De Rooij1, P A De Koning Gans, R A Roos
1MGC-Department of Human Genetics, Sylvius Laboratory, Leiden University, The Netherlands.
Insights
Huntington disease (HD) involves a (CAG)n repeat expansion in the huntingtin gene. While some somatic expansion occurs in affected brain regions, it
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene.
- The mutation is an expansion of a polymorphic (CAG)n repeat in the 5' region of the huntingtin gene.
- The selective neuronal loss in specific brain regions (caudate nucleus and putamen) in HD is not fully explained by the gene's widespread expression.
Purpose of the Study:
- To investigate the role of somatic expansion of the (CAG)n repeat in the differential neuropathology of Huntington disease.
- To compare the length of the (CAG)n repeat in various brain regions affected by HD and in unaffected tissues.
Main Methods:
- Analysis of the (CAG)n repeat length in different brain regions (affected and unaffected) of HD patients.
- Comparison of repeat lengths between affected brain areas, cerebellum, and peripheral blood samples.
Main Results:
- No significant differences in (CAG)n repeat length were observed between severely and mildly affected brain regions in HD.
- A minor increase in (CAG)n repeat length was detected when comparing affected brain samples to cerebellum or peripheral blood.
Conclusions:
- Somatic amplification of the (CAG)n repeat appears to occur in affected brain areas of Huntington disease.
- The observed differences in repeat length between affected and unaffected brain regions are too small to explain the selective neuronal degeneration characteristic of HD.
Abstract:
The mutation causing Huntington disease (HD) has been identified as an expansion of a polymorphic (CAG)n repeat in the 5' part of the huntingtin gene. The specific neuropathology of HD, viz. selective neuronal loss in the caudate nucleus and putamen, cannot be explained by the widespread expression of the gene. Since somatic expansion is observed in affected tissue in myotonic dystrophy, we have studied the length of the (CAG)n repeat in various regions of the brain. Although we have not found clear differences when comparing severely and mildly affected regions, we have observed a minor increase in repeat length upon comparison of affected brain samples with cerebellum or peripheral blood. Hence, although further somatic amplification seems to occur in affected areas of the brain, the differences between affected and unaffected regions are too small to make this mechanism an obvious candidate for the cause of differential neuronal degeneration in HD.