Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance

S. Zoppi, M. Marcelli, J. P. Deslypere, Jim Griffin III, J. D. Wilson, M. J. McPhaul

Research output: Contribution to journalArticle

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Abstract

In some subjects with genetic and endocrine evidence of androgen resistance, no defect is demonstrable in the binding of androgen to its receptor in cultured genital skin fibroblasts. We have defined the molecular defect in the androgen receptor in four unrelated subjects in this category (termed receptor positive) with the phenotype of compete or incomplete testicular feminization. In these patients we detected amino acid substitutions in either exon 2 or exon 3, which encodes the DNA-binding domain of the androgen receptor. In one patient with incomplete testicular feminization, two separate mutations were present in exon 3. Introduction of these amino acid substitutions into the androgen receptor-coding segment leads to the expression of receptor proteins that bind ligand in a normal fashion but do not activate the transcription of the androgen-responsive mouse mammary tumor virus promoter. Mobility shift assays using androgen receptor fusion proteins produced in E. coli indicate that these mutations impair binding of the receptor to specific DNA sequences. In the subject with incomplete testicular feminization, a Ser-Gly substitution at amino acid residue 595 is able to partially restore DNA-binding activity to a mutant receptor protein that carries an Arg-Pro substitution at position 615. These findings indicate that mutations in amino acid residues crucial to the binding of the androgen receptor to target DNA sequences are a common cause of receptor-binding positive androgen resistance and that variable impairment of DNA binding can lead to distinctive phenotypes.

Original languageEnglish (US)
Pages (from-to)409-415
Number of pages7
JournalMolecular Endocrinology
Volume6
Issue number3
StatePublished - Mar 1992

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Androgen Receptors
Amino Acid Substitution
Androgens
Androgen-Insensitivity Syndrome
DNA
Exons
Mutation
arginylproline
Mouse mammary tumor virus
Phenotype
Electrophoretic Mobility Shift Assay
Mutant Proteins
Carcinogens
Proteins
Fibroblasts
human AR protein
Escherichia coli
Ligands
Amino Acids
Skin

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance. / Zoppi, S.; Marcelli, M.; Deslypere, J. P.; Griffin III, Jim; Wilson, J. D.; McPhaul, M. J.

In: Molecular Endocrinology, Vol. 6, No. 3, 03.1992, p. 409-415.

Research output: Contribution to journalArticle

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