Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy

Michael J. McPhaul, Marco Marcelli, Wayne D. Tilley, Jim Griffin III, Rosario F. Isidro-Gutierrez, Jean D. Wilson

Research output: Contribution to journalArticle

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We have examined the nature of the mutant androgen receptor in a family with a severe defect in virilization associated with a qualitative defect in receptor function. The androgen receptor gene in this family contains two structural alterations: a single nucleotide substitution at position 2444 in exon 5 (adenosine → guanosine) that converts tyrosine 761 to a cysteine residue and a shortened glutamine homopolymeric segment in exon 1 that encodes 12 rather than the usual 20-22 glutamines. A family study was performed using polymerase chain reaction amplification of the glutamine-rich segment, and it was shown that the sister of the proband does not carry the mutant allele. The effects of these two mutations on the function of the androgen receptor were studied by introducing the changes, individually and in combination, into cDNAs encoding the normal human androgen receptor and analyzing the receptor protein produced after transfection of the cDN As into eukaryotic cells. The presence of a cysteine residue at position 761 causes rapid dissociation of dihydrotestosterone from the receptor protein. Marked thermolability of the transfected receptor protein, however, was demonstrable only upon introduction of an androgen receptor cDNA containing both the partial deletion of the glutamine homopolymeric segment and a cysteine residue at position 761. Likewise, the ability of the receptor to stimulate a reporter gene is strikingly diminished only when both alterations are present, suggesting that the shortened glutamine homopolymeric segment amplifies the impairment of receptor function caused by the tyrosine to cysteine substitution.

Original languageEnglish (US)
Pages (from-to)1413-1421
Number of pages9
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - Apr 1991



  • Androgen receptor
  • Androgen resistance
  • Mutation

ASJC Scopus subject areas

  • Medicine(all)

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