The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

• Published in: Nucleic acids research Vol. 22; no. 15; pp. 3181 - 3186
• Main Authors: Chamberlain, Nancy L., Driver, Erika D., Miesfeld, Roger L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 11.08.1994
• Subjects: Animals; Base Sequence; Biological and medical sciences; Blotting, Western; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Genes, Reporter; Haplorhini; Humans; Huntington Disease - genetics; Kidney; Medical sciences; Molecular Sequence Data; Motor Neurons - metabolism; Muscular Atrophy, Spinal - genetics; Mutation; Neurology; Receptors, Androgen - genetics; Receptors, Androgen - physiology; Repetitive Sequences, Nucleic Acid; Transcription, Genetic; Transcriptional Activation; Transfection; X Chromosome; Human; Ligand binding; Androgen; Transcription; Pathogenesis; Repeated sequence; N terminal peptide; In vitro; Structure function relationship; Animal; Mutation; Sex steroid hormone; Hormonal receptor
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/22.15.3181

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.