Androgens in Health and Disease.pdf - E Library

Chapter 6/Mutations of the AR 113
methionine 189. Subsequent experiments demonstrated that this truncated receptor protein
(lacking amino acids 1–189) is synthesized in normal cells and is analogous to the
A-form of the progesterone receptor (57). Studies in heterologous cells have established
that the phenotype observed in affected individuals within this family (complete testicular
feminization) is the result of a combination of reduced amounts androgen receptor
and a reduced function of the AR that is synthesized (58).
The patient with partial AIS described by Choong et al. identified a completely distinct
mechanism by which reduced levels of apparently normal AR could be expressed
(59). In this individual, a single-nucleotide substitution was identified that resulted in the
replacement of the second amino acid residue of the AR open reading frame (D2K).
Using functional and in vitro assays, the authors presented evidence that although a
subtle increase in the rate of ligand dissociation was observed, the reduced level of AR
expressed as a result of decreased efficiency of translational initiation was the more
important determinant of disturbed AR action in this pedigree.
It is likely that mutations identified within this category will be quite heterogeneous,
as the mutations may result in reduced quantities of normal AR. Alternatively, samples
placed within this category may express reduced levels of AR that exhibits subtle alterations
not detected in monolayer-binding assays performed on fibroblast cultures.
MINIMAL DEFECTS OF VIRILIZATION CAUSED BY MUTATIONS
OF THE ANDROGEN RECEPTOR
A small number of AR mutations have been identified in patients exhibiting more
subtle disturbances of androgen action. These generally have been associated with either
a more subtle phenotype (undervirilized male) or infertility.
Tsukada et al. were the first to report an AR mutation in such a pedigree with androgen
resistance and undervirilization and preserved fertility (60). These workers identified an
amino acid substitution (L790F) in the LBD of the AR. In ligand-binding assays, the
mutant receptor displayed thermal instability and altered kinetics of androgen binding.
When analyzed in transfection assays, AR function was observed to be only slightly
reduced compared to the normal AR. As would be expected for a mutation causing a
qualitative abnormality of the AR (see above discussion), the defective function of this
mutant AR was most pronounced at lower hormone concentrations.
Among the most intriguing of AR defects are those implicated in causing isolated
defects of spermatogenesis. To date, only a small number of such mutant ARs have been
reported. In each instance, these mutations have been identified during the evaluation of
patients presenting with azoospermia or oligospermia (61–63). In each instance, the
mutant AR was found to exhibit only slightly diminished function using transfection
assays. In one instance, the mutation was found to cause decreased association of the
ligand-activated mutant AR with the coactivator TIF2 in two-hybrid assays (62,63) . The
mutations identified are diverse (R788S, Q798E, M886V) and none are directly in the
formation of the ligand-binding pocket. Two of the substitutions are positioned in helix
7 (R788S, Q798E) and one (M886V) is located at the carboxyl-terminal end of helix 10/
11 of the AR LBD. The only property that is clearly shared by these mutations is that each
results in only small decreases of AR function. It is interesting to note that no mutations
in the DBD of the AR have been described that cause such a phenotype.
In addition to substitution mutations in the AR LBD, increases in the length of the
glutamine repeat in the amino terminus of the AR have been associated with an increased