The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function
Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order t...
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Published in | Nucleic acids research Vol. 22; no. 15; pp. 3181 - 3186 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Oxford University Press
11.08.1994
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Subjects | |
Online Access | Get full text |
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Summary: | Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease. |
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Bibliography: | istex:5AAE05A4D31DE8EA15824B2E4F0D6B8F69FD727D ark:/67375/HXZ-5NT5T49K-L To whom correspondence should be addressed 1Department of Biochemistry ArticleID:22.15.3181 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0305-1048 1362-4962 |
DOI: | 10.1093/nar/22.15.3181 |