Native Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy

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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Nuclear receptors and disease: androgen receptor

Essays in Biochemistry ◽

10.1042/bse0400121 ◽

2004 ◽

Vol 40 ◽

pp. 121-136 ◽

Cited By ~ 24

Author(s):

Bruce Gottlieb ◽

Lenore K Beitel ◽

Jianhui Wu ◽

Youssef A Elhaji ◽

Mark Trifiro

Keyword(s):

Androgen Receptor ◽

Dna Sequences ◽

Muscular Atrophy ◽

Binding Domain ◽

Spinobulbar Muscular Atrophy ◽

Precise Control ◽

Research Areas ◽

Regulatory Dna Sequences ◽

Active Research ◽

Regulatory Dna

The androgen receptor (AR) protein regulates transcription of certain genes. Usually this depends upon a central DNA-binding domain that permits the binding of androgen–AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal ligand-binding domain and an Nterminal transcription modulatory domain. These N- and C-terminal domains interact directly, and with co-regulatory, non-receptor proteins, to exert precise control over a gene’s transcription rate. The precise roles of these proteins are active research areas. Severe X-linked AR gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones yield a wide phenotypic spectrum sometimes among siblings. Different phenotype expressivity may reflect variability of ARinteractive proteins. Mutations occur throughout the AR but are concentrated in specific areas of the gene known as hot spots. A number of these mutations of somatic origin are associated with prostate cancer. N-terminal polyglutamine (polyGln) tract expansion reduces AR transactivation, and when there are more than 38 glutamine residues it causes spinobulbar muscular atrophy, a motor neuron disease, due to a gain of function. Variations in polyGln tract length have been associated as risk factors with prostate, breast, uterine, endometrial and colorectal cancer, as well as male infertility.

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