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Androgen Resistance Associated with a Mutation of the Androgen Receptor at Amino Acid 772 (ArgCys) Results from a Combination of Decreased Messenger Ribonucleic Acid Levels and Impairment of Receptor Function^*

MARCO MARCELLI, WAYNE D. TILLEY, SONIA ZOPPI, JAMES E. GRIFFIN, JEAN D. WILSON and MICHAEL J. MCPHAUL

Department of Internal Medicine, University of Texas Southwestern Medical Center Dallas, Texas 75235–8857

Address requests for reprints to: Dr. Michael J. McPhaul, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235–8857.

Analysis of the nucleotide sequence of the coding segment of the androgen receptor gene in a patient (N105) with the receptor-negative form of complete testicular feminization has revealed a single substitution (CGCTGC) at nucleotide 2476. This alteration results in the conversion of an arginine at amino acid 772 to a cysteine. Introduction of this mutation into an androgen receptor cDNA and transfection of the mutant cDNA into COS cells result in the production of a receptor protein with an alteration in the apparent K_d of ligand binding (3 nM) compared to that of the normal androgen receptor (0.5 nM). The mutant receptor protein predicted for patient N105 also demonstrates thermal instability of ligand binding that is not associated with quantitative or qualitative changes in the immunoreactive androgen receptor protein. When assayed in cotransfection experiments using a mouse mammary tumor virus-chloramphenicol acetyl transferase reporter system, the N105 receptor protein appears to be about a tenth as active as the control receptor. These functional characteristics do not appear sufficient to account for the phenotype of complete testicular feminization and do not explain the profound deficiency of androgen receptor in cultured skin fibroblasts. Quantitative Si nuclease protection assays reveal that the level of androgen receptor mRNA in fibroblasts from patient N105 is markedly reduced. These results suggest that the phenotype in patient N105 is due to two effects of the nucleotide substitution at residue 2476: the replacement of a crucial amino acid (772) in the hormone-binding domain that impairs the function of any receptor molecules formed and a decrease in the level of androgen receptor mRNA.

^* This work was supported by Grant DK-03892 from the NIH, a Basil O’Connor Award from the March of Dimes (no. 5–694), the Medical Life and Health Insurance Medical Research Fund, the Charles E. Culpeper Foundation, Inc., the Welch Foundation (no. I-1090), and a grant from the Perot Family Foundation.

Recipient of a C. J. Martin Fellowship from the National Health and Medical Research Council of Australia.

Culpeper Medical Scholar.

Received October 30, 1990.

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