Point mutations detected in the androgen receptor gene of three men with partial androgen insensitivity syndrome

Abstract

Patients 1 and 2 are unrelated although they have an identical point mutation in their androgen receptor gene. A patient with complete androgen insensitivity syndrome has been reported to have a defect at the same position causing the amino acid substitution of methionine for valine. Therefore we confirm that the nature of the amino acid change in the peptide sequence of the androgen receptor as well as its location within the protein, can have a profound effect on the phenotypic severity of androgen resistance. Studies on mutated receptors from individuals with a wide range of degrees of androgen resistance may enable us to construct a map of the key amino acids in the different domains of the protein.

Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high‐dose testosterone in patients with partial androgen insensitivity syndrome

“…3b). This mutation was previously reported as amino acid 607 (Saunders et al, 1992) based on numbering of AR by Chang et al (1988). In exon 1, the glutamine repeat region contained 23 repeated codons.…”

“…Genomic DNA was extracted from 10 ml of citrated peripheral blood (Grimberg et al, 1989) and individual exons of the androgen receptor gene were amplified by polymerase chain reaction (PCR) as previously described (Saunders et al, 1992) but using primers published by Lubahn et al (1989). Screening of amplified portions of the AR for the presence of mutations was performed by the technique of denaturing gradient gel electrophoresis (DGGE; De Bellis et al, 1992) which separates DNA fragments on the basis of their sequence.…”

Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene

“…The characterization of mutations in the AR gene can serve as a reliable tool for the diagnosis and molecular subclassification of AIS [2,3,11,13,26]. In contrast to biochemical studies, which require genital skin biopsies, molecular genetic analysis can be achieved as a minimally invasive procedure from blood leucocyte DNA.…”

“…The substitution of valine by leucine at position 866 has exclusively been reported to be associated with partial AIS [11,17,26]. Extensive characterization of this mutation in genital skin fibroblasts revealed that in the presence of high dihydrotestosterone concentrations, transcriptional activation by the mutant receptor approached that of the normal receptor [17], indicating dependency of receptor function on the actual androgen concentration.…”

“…In the 11 control patients (patients [24][25][26][27][28][29][30][31][32][33][34], in whom a cause other than AIS could be found to explain genital maldevelopment, no nucleotide variations were found in the AR gene. SHBG decreased in these patients to a mean of 51.4% ± 2.1% (median 49.6%, range 35.6%-62.1%) of the initial value, which was within the normal range (i.e.…”