Expansion of the number of CAG repeats in the human ataxin-1 gene are the mutational cause of Spinocerebellar Ataxia Type 1 (SCA1). This proposal describes studies aimed at understanding when and how the CAG repeats change in repeat number. We will examine sperm DNA from ataxia patients and from normal controls to measure the frequency and size changes in the CAG repeats during male gametogenesis when most changes are known to occur. We will also be examining CAG repeat lengths in lymphoblastoid cells made from ataxic patients' lymphocytes to learn if some individuals are more prone to repeat instability than others. These studies will be extended to transgenic mice carrying the human ataxin-1 gene to learn whether CAG repeats which are unstable in humans are also unstable in this mammal. A major portion of the study is the establishment of two in vitro systems for examining CAG repeat instability. One system will be in cultured primate and human cells and the other in yeast cells. In both systems we will create a gene with a CAG repeat cassette and vary the number of CAG repeats in the cassette. After transfection or transformation of the cassette-containing gene into cells, we will screen or select for mutational changes in repeat length. By varying the number of repeat copies, the sequence of repeat copies and the placement of repeat copies, we will learn when repeat sequences become unstable. Furthermore, the yeast cell system will be used to find mutations of yeast genes which alter the stability of trinucleotide repeats. Such mutations define genes whose identity can help in determining the mechanism by which trinucleotide repeats expand.

Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Sidtis, John J; Strother, Stephen C; Groshong, Ansam et al. (2010) Longitudinal cerebral blood flow changes during speech in hereditary ataxia. Brain Lang 114:43-51
Sidtis, John J; Gomez, Christopher; Groshong, Ansam et al. (2006) Mapping cerebral blood flow during speech production in hereditary ataxia. Neuroimage 31:246-54
Arnold, J B; Liow, J S; Schaper, K A et al. (2001) Qualitative and quantitative evaluation of six algorithms for correcting intensity nonuniformity effects. Neuroimage 13:931-43
Muley, S A; Strother, S C; Ashe, J et al. (2001) Effects of changes in experimental design on PET studies of isometric force. Neuroimage 13:185-95
Liow, J S; Zhou, L (2000) Evaluating performance of reconstruction algorithms for 3-D [15O] water PET using subtraction analysis. IEEE Trans Med Imaging 19:522-31
Sidtis, J J (2000) From chronograph to functional image: what's next? Brain Cogn 42:75-7
Frutiger, S A; Strother, S C; Anderson, J R et al. (2000) Multivariate predictive relationship between kinematic and functional activation patterns in a PET study of visuomotor learning. Neuroimage 12:515-27
Day, J W; Schut, L J; Moseley, M L et al. (2000) Spinocerebellar ataxia type 8: clinical features in a large family. Neurology 55:649-57
Moseley, M L; Schut, L J; Bird, T D et al. (2000) SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Hum Mol Genet 9:2125-30
Clark, H B; Orr, H T (2000) Spinocerebellar ataxia type 1--modeling the pathogenesis of a polyglutamine neurodegenerative disorder in transgenic mice. J Neuropathol Exp Neurol 59:265-70

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