Complete Androgen Insensitivity Syndrome Characterized by Increased Concentration of a Normal Androgen Receptor in Genital Skin Fibroblasts*

Abstract

Two siblings with the classical phenotype of complete androgen insensitivity syndrome (CAIS) and increased total cellular androgen receptor concentrations in genital skin fibroblasts (GSF) are described. Testosterone biosynthesis was normal, and there was no evidence of 5 alpha-reductase deficiency. Specific binding of [3H]dihydrotestosterone ([3H]DHT) in GSF was 7 SD above the mean value in normal fibroblast strains [maximum binding, 775 +/- 185 X 10(-18) mol/micrograms DNA (mean +/- SD)]. Binding at 40 C was stable, and the androgen-receptor complex dissociated at a normal rate (t1/2, 85 min). The androgen-receptor complex from GSF cytosol sedimented at 5-6S on sucrose density gradients in the presence of sodium molybdate. In a whole cell binding assay, the percentage of [3H]DHT that bound to a crude nuclear pellet was 60%. Preincubation of GSF with 2 nM [3H]DHT for 20 h before the standard 1-h whole cell binding assay produced a further augmentation in elevated total cellular androgen receptor concentrations. A new variant of CAIS is described which is characterized by an increased concentration of androgen receptors that appear to be quantitatively and qualitatively normal. Augmentation of the receptor by androgen suggests that the gene coding for the androgen receptor is intact and does not account for the androgen insensitivity.

Androgen Receptors in Bone-Forming Tissue

“…The first five publications detailing the localisation of AR in mesenchymatous cells demonstrated AR mainly in the cytoplasmic fraction [12, 13, 14, 15, 16]. All their studies used bulk preparations [12, 13, 14, 15, 16].…”

The Fibroblast as a Model for Androgen Resistant States

“…For example, the two sisters reported with the complete form and supranormal receptor levels (Hughes & Evans, 1986) had an identical clinical phenotype to the typical AR -ve patient with complete androgen insensitivity. Several laboratories have sought to explain the pathogenesis of AR +ve androgen insensitivity by studying qualitative functions of the androgenreceptor complex.…”

“…4a) were ARve; of the remaining five patients who were AR +ve, four patients had supranormal androgen-receptor levels. The characteristics of androgen-receptor binding were studied in detail in two sisters with this phenotype but no abnormality was demonstrated (Hughes & Evans, 1986). Only 7% of patients with partial androgen insensitivity (Fig.…”

Androgen Insensitivity Syndrome (AIS)

“…Any mutation of the cysteine residues would severely disrupt the zinc fi nger module structure and result in complete androgen insensitivity syndrome despite androgens binding normally to the ligandbinding domain. 59,60 An α helix in the fi rst zinc module (the proximal box) enters the major groove of doublestranded DNA and forms specifi c basepair contacts that are identical for all classical steroid receptors. 61 Figure 2 shows the results of an androgen receptor functional assay for three diff erent natural mutants when valine is replaced at codon 582 in the fi rst zinc module.…”