Genetic aspects of the androgen receptor in human androgen insensitivity

The AR is a ligand-activated transcription factor of androgen-regulated genes. It is commonly assumed - though not experimentally proven to date - that a controlled temporal and spatial expression of androgen-regulated genes during early embryogenesis provokes a distinct spectrum of functional and structural alterations of the internal and external genitalia, ultimately resulting in the irreversible formation of the normal male phenotype (Holterhus etal. 2003).

The ARbelongs to the intracellular family of structurally related steroid hormone receptors. Transcriptional regulation through the AR is a complex multistep process involving androgen binding, conformational changes of the AR protein, receptor phosphorylation, nuclear trafficking, DNA binding, cofactor interaction and finally transcription activation. It is now more than 15 years ago that the human AR gene was cloned by several groups and mapped to Xq11-12 (Chang et al. 1988; Lubahn etal. 1988a; 1988b; Tilley etal. 1989; Trapman etal. 1988). It spans approximately 90 kilobases (kb) and comprises 8 exons, named 1-8 or A-H. Transcription of the AR gene and subsequent splicing usually results in distinct AR-mRNA populations in genital fibroblasts. Translation of the mRNA into the AR protein usually leads to a product migrating at about 110 kDa in Western immunoblots comprising between 910 to 919 amino acids.

The AR shares its particular modular composition of three major functional domains with the other steroid hormone receptors. A large N-terminal domain precedes the DNA-binding domain, followed by the C-terminal ligand-binding domain. Additional functional subdomains could be identified by in vitro investigation of artificially truncated, deleted or point mutated ARs (for review see Quigley etal. 1995). Upon entering target cells, androgens interact very specifically with the ligand-binding pocket of the AR. This initiates an activation cascade with conformational changes and nuclear translocation of the AR. Prior to receptor binding to target DNA, homodimerization of two AR proteins occurs in a ligand-dependent manner. This is mediated by distinct sequences within the second zinc finger of the DNA-binding domain as well as through specific structural N-C-terminal interactions. The AR-homodimer binds to hormone responsive elements (HRE) which usually consists of two palindromic (half-site) sequences within the promoter of androgen-regulated genes. Through chromatin remodelling, direct interaction with other transcription factors and specific coactivators and corepres-sors, a steroid-receptor specific modulation of the assembly of the preinitiation complex is achieved, resulting in specific activation or repression of target gene transcription.

More than 300 different mutations have been identified in AIS to date (http://ww2.mcgill.ca/androgendb/). Extensive structural alterations of the AR can result from complete or partial deletions of the AR gene. Smaller deletions may introduce a frame shift into the open reading frame leading to a premature stop codon downstream of the mutation. Similar molecular consequences arise from the direct introduction of a premature stop codon due to point mutations. Such alterations usually lead to severe functional defects of the AR and are associated with CAIS. Extensive disruption of the AR protein structure can also be due to mutations leading to aberrant splicing of the AR m-RNA (Hellwinkel et al. 1999; 2001). However, as aberrant splicing can be partial and thus enable expression of the wild type AR, the AIS phenotype is not necessarily CAIS but may also present with PAIS (Hellwinkel et al. 2001). The most common molecular defects of the AR gene are missense mutations. They may either result in CAIS or in PAIS because of complete or partial loss of AR function (Hiort et al. 1996). Mutations within the ligand-binding domain may alter androgen binding but may in addition influence dimerization due to disruption of N-C-terminal structural interactions. Mutations within the DNA-binding domain can affect receptor binding to target DNA. Recently, a first female patient with complete AIS without an AR gene mutation but with clear experimental evidence for an AR-coactivator deficiency as the only underlying molecular mechanism of defective androgen action was reported (Adachi et al. 2000). Cofactors of the AR will presumably play a pivotal role in the understanding of the phenotypic variability in AIS. So far, only a few mechanisms contributing to the phenotypic diversity in AIS were identified in affected individuals. A striking phenotypic variability in a family with partial AIS has been attributed to differential expression of the 5a reductase type 2 enzyme in genital fibroblasts (Boehmer et al. 2001). Another mechanism may be the combination of varying androgen levels during early embryogenesis and partially inactivating mutations of the ligand-binding domain (Holterhus etal. 2000).

Moreover, post-zygotic mutations of the AR gene resulting in a somatic mosaicism of mutant and wild-type AR genes can contribute to modulation of the phenotype. This can result in a higher degree ofvirilization than expected from the AR mutation alone because of the expression of the wild type AR in a subset of somatic cells. Because at least one third of all de novo mutations of the AR gene occur at the post zygotic stage, this mechanism is not only important for phenotypic variability in AIS but also crucial for genetic counselling (Hiort etal. 1998).

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