Androgen resistance due to mutation of the androgen receptor.

The androgen receptor (AR) is a 'one-stop' signal transduction system that is the core of the intracellular androgen-response apparatus. It is an androgen-regulated, DNA-binding protein that regulates the expression of certain target genes, primarily at the transcriptional level. Mutations at the X-linked AR locus cause deficient or defective AR activity and, thereby, an extraordinarily wide spectrum of clinical androgen resistance. At one extreme, the affected 46,XY person is an infertile phenotypic female; at the other, he is a phenotypic male who may even be fertile, yet have gynecomastia or other focal signs of postpubertal subvirilization. We have identified 32 proven or putatively pathogenic alterations in the AR gene of 38 androgen-resistant families. This permits heterozygote detection and prenatal diagnosis whenever relevant. Most of the mutations affect the AR's androgen-binding domain, partly because our search has been targetted on those whose genital skin fibroblasts have impaired androgen-binding activities. The AR is a prototypic member of a subfamily that includes the receptors for progesterone, glucocorticoid, and mineralocorticoid. Observations that correlate AR genotype with clinical and receptor phenotypes of androgen resistance will help to generate a fine structure-function map of the AR and its close relatives. Constitutional variation in androgen sensitivity, that may be restricted to an organ (or organ system), could contribute to the pathogenesis of certain diseases whose sex ratio departs significantly from one.