Please use this identifier to cite or link to this item: https://doi.org/10.1016/S0303-7207(97)00229-3
Title: Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain
Authors: Yong, E.L. 
Tut, T.G.
Ghadessy, F.J. 
Ratnam, S.S. 
Prins, G.
Keywords: 3-D structure
Androgen receptor
Issue Date: 1998
Citation: Yong, E.L., Tut, T.G., Ghadessy, F.J., Ratnam, S.S., Prins, G. (1998). Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain. Molecular and Cellular Endocrinology 137 (1) : 41-50. ScholarBank@NUS Repository. https://doi.org/10.1016/S0303-7207(97)00229-3
Abstract: Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient's fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-α), has been crystalized, allowing comparison of aligned amino acid sequences of RXR-α and AR. The mutation, N758T, lies in a predicted linker region between the fifth α-helix (H5) and the first β-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.
Source Title: Molecular and Cellular Endocrinology
URI: http://scholarbank.nus.edu.sg/handle/10635/37142
ISSN: 03037207
DOI: 10.1016/S0303-7207(97)00229-3
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