This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nguyen, D. Articles by Mader, S. Search for Related Content PubMed PubMed Citation Articles by Nguyen, D. Articles by Mader, S.

A G577R Mutation in the Human AR P Box Results in Selective Decreases in DNA Binding and in Partial Androgen Insensitivity Syndrome

Department of Biochemistry (D.N., S.V.S., E.R., S.C., S.M.), Université de Montréal, Montréal, Québec H3C 3J7, Canada; Departments of Biology and Pediatrics (L.P.,), Human Genetics (L.P., M.T.), and Medicine (M.T., S.M.), McGill University, Montréal, Québec H3G 1Y6, Canada; Lady Davis Institute for Medical Research (B.G., L.P., M.T.), Sir M. B. Davis-Jewish General Hospital, Montréal, Québec H3T 1E2, Canada; and McGill Center for Translational Research in Cancer (S.M.), McGill University, Montréal, Québec H3G 1Y6, Canada

Address all correspondence and requests for reprints to: Dr. Sylvie Mader, Département de Biochimie, Faculté de Médecine, Université de Montréal, C.P. 6128 Succursale Centre Ville, Montréal, Québec H3C 3J7 Canada. E-mail: sylvie.mader{at}umontreal.ca

We have characterized a novel mutation of the human AR, G577R, associated with partial androgen insensitivity syndrome. G577 is the first amino acid of the P box, a region crucial for the selectivity of receptor/DNA interaction. Although the equivalent amino acid in the GR (also Gly) is not involved in DNA interaction, the residue at the same position in the ER (Glu) interacts with the two central base pairs in the PuGGTCA motif. Using a panel of 16 palindromic probes that differ in these base pairs (PuGNNCA) in gel shift experiments with either the AR DNA-binding domain or the full length receptor, we observed that the G577R mutation does not induce binding to probes that are not recognized by the wild-type AR. However, binding to the four PuGNACA elements recognized by the wild-type AR was affected to different degrees, resulting in an altered selectivity of DNA response element recognition. In particular, AR-G577R did not interact with PuGGACA palindromes. Modeling of the complex between mutant AR and PuGNACA motifs indicates that the destabilizing effect of the mutation is attributable to a steric clash between the Cß of Arg at position 1 of the P box and the methyl group of the second thymine residue in the TGTTCPy arm of the palindrome. In addition, the Arg side chain can interact with G or T at the next position (PuGCACA and PuGAACA elements, respectively). The presence of C is not favorable, however, because of incompatible charges, abrogating binding to the PuGGACA element. Transactivation of several natural or synthetic promoters containing PuGGACA motifs was drastically reduced by the G577R mutation. These data suggest that androgen target genes may be differentially affected by the G577R mutation, the first natural mutation characterized that alters the selectivity of the AR/DNA interaction. This type of mutation may thus contribute to the diversity of phenotypes associated with partial androgen insensitivity syndrome.

This article has been cited by other articles:

				O. A. O'Mahony, M. P. Steinkamp, M. A. Albertelli, M. Brogley, H. Rehman, and D. M. Robins Profiling Human Androgen Receptor Mutations Reveals Treatment Effects in a Mouse Model of Prostate Cancer Mol. Cancer Res., November 1, 2008; 6(11): 1691 - 1701. [Abstract] [Full Text] [PDF]

				D. Nguyen, M. Bail, G. Pesant, V. N. Dupont, E. Rouault, J. Deschenes, W. Rocha, G. Melancon, S. V. Steinberg, and S. Mader Rational design of an estrogen receptor mutant with altered DNA-binding specificity Nucleic Acids Res., May 11, 2007; 35(10): 3465 - 3477. [Abstract] [Full Text] [PDF]

				M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al. Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12 Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816. [Abstract] [Full Text] [PDF]

				Y. Zhang, N. Champagne, L. K. Beitel, C. G. Goodyer, M. Trifiro, and A. LeBlanc Estrogen and Androgen Protection of Human Neurons against Intracellular Amyloid {beta}1-42 Toxicity through Heat Shock Protein 70 J. Neurosci., June 9, 2004; 24(23): 5315 - 5321. [Abstract] [Full Text] [PDF]

				V. Bourdeau, J. Deschenes, R. Metivier, Y. Nagai, D. Nguyen, N. Bretschneider, F. Gannon, J. H. White, and S. Mader Genome-Wide Identification of High-Affinity Estrogen Response Elements in Human and Mouse Mol. Endocrinol., June 1, 2004; 18(6): 1411 - 1427. [Abstract] [Full Text] [PDF]