Male Pseudohermaphroditism Caused by Mutations of the Human Androgen Receptor1

Abstract

A exert their effects in mediating the development of the normal male phenotype via a single receptor protein, the androgen receptor (AR), which is encoded on the X chromosome. Abnormalities that alter the function of this receptor result in a range of abnormalities of male phenotypic development. These phenotypes range from that of normal females (complete testicular feminization, complete androgen insensitivity) to those that are characterized by only minor degrees of undervirilization and/or infertility. The defects of receptor function that have been characterized fall into two major categories. The first are those that disrupt the primary sequence of the AR. These mutations can be due to the introduction of premature termination codons, frameshift mutations, deletions or insertions, or alterations of RNA splicing. The ARs that are produced as a result of these genetic alterations are uniformly associated with complete androgen resistance. The second, and most common type of AR mutation, is that which is caused by single amino acid substitutions within the AR protein. In contrast to the preceding category, mutations of this type may result in the full spectrum of androgen resistant phenotypes. These mutations cluster in two important domains of the receptor protein: the DNAand the hormonebinding domains. Substitutions in the DNA-bindingdomain act to impair the ability of the AR to recognize target sequences within or adjacent to androgen-responsive genes. The degree of impairment of DNA binding is directly related to the degree of impairment of receptor function. Amino acid replacements within the hormone-binding domain can have a range of effects on the binding of ligand by the AR. In some instances, the capacity to bind hormone is completely abolished, while in other instances, only subtle qualitative abnormalities of ligand binding can be detected. In all mutants containing amino acid substitutions within the hormone-binding domain, the ability to form stable ARhormone complexes determines the amount of receptor function that remains. The phenotype that is observed does not appear to correlate with the identity of the residue that is mutated or its replacement. Instead, the phenotype appears to be a reflection of the degree to which androgen action is impaired. As the level of mutant AR protein expressed is similar to that observed in normal subjects, this usually reflects the degree to which AR function is altered. The male hormones, androgens, control wide range of processes in the male during embryonic development and in postnatal life. During embryogenesis, the concerted actions of testosterone (T) and 5a-dihydrotestosterone (DHT) are critical to the virilization of the Wolffian duct structures and the external genitalia. Genetic defects that impair androgen synthesis or action will result in abnormalities of male phenotypic development in 46, XY individuals with testes (male pseudohermaphroditism). Among the potential etiologies, defects of the AR are among the most common.