Correction: Corrigendum: Reduced transcriptional regulatory competence of the androgen receptor in X–linked spinal and bulbar muscular atrophy

Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino-terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy. We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (ΔQ) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution, the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in α-helix structure, while deletion of the repeat resulted in a small loss of α-helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte trimethylamine N-oxide. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after the deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition, this polypeptide not only showed enhanced binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonic acid but was more sensitive to urea-induced unfolding. Taken together, these findings support the view that the presence and length of the poly-Q repeat modulate the folding and structure of the AR-NTD.

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Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy

Biochemical Society Transactions ◽

10.1042/bst0290222 ◽

2001 ◽

Vol 29 (2) ◽

pp. 222-227 ◽

Cited By ~ 14

Author(s):

I. J. McEwan

Keyword(s):

Androgen Receptor ◽

Spinocerebellar Ataxia ◽

Muscular Atrophy ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Diverse Range ◽

Disease States ◽

Associated Proteins ◽

Spinal Bulbar Muscular Atrophy ◽

Clinical Conditions

The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.

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Assessment of Androgen Receptor Function in Genital Skin Fibroblasts Using a Recombinant Adenovirus to Deliver an Androgen-Responsive Reporter Gene1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.6.3966 ◽

1997 ◽

Vol 82 (6) ◽

pp. 1944-1948

Author(s):

Michael J. McPhaul ◽

Hans-Udo Schweikert ◽

Diane R. Allman

Keyword(s):

Androgen Receptor ◽

Recombinant Adenovirus ◽

Muscular Atrophy ◽

Normal Subjects ◽

Testicular Feminization ◽

Spinobulbar Muscular Atrophy ◽

Vitro Binding ◽

The Family ◽

Androgen Resistance

Abstract Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.

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