Nucleic Acids Research, 1994, Vol. 22, No. 15 3181-3186
© 1994
MOLECULAR BIOLOGY |
The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function
*To whom correspondence should be addressed
Received March 24, 1994. Revised June 16, 1994. Accepted June 16, 1994.
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.
1Department of Biochemistry
3Undergraduate Biology Research Program
124Department of Biochemistry, Department of Molecular and Cellular Biology and The Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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