Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (Arg→Cys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function

Marco Marcelli, Wayne D. Tilley, Sonia Zoppi, Jim Griffin III, Jean D. Wilson, Michael J. McPhaul

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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 (CGC→TGC) at nucleotide 2476. This alteration results in the conversion of an arginine at amino acid 772 to a cysteme. 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 Kd 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 S1 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.

Original languageEnglish (US)
Pages (from-to)318-325
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume73
Issue number2
StatePublished - Aug 1991

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Fingerprint

Dive into the research topics of 'Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (Arg→Cys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function'. Together they form a unique fingerprint.

Cite this