Androgen Insensitivity

Abstract

Androgen insensitivity is an X‐linked disorder of defective or absent virilisation in 46, XY individuals due to complete or partial resistance to androgens in androgen‐dependent tissues and organs. The syndrome is part of a scala of disorders of sex development (DSD). The molecular cause of the syndrome is mutations in the androgen receptor gene (locus: Xq11.2–12), resulting either in absence of an androgen receptor protein or in production of a mutant androgen receptor protein with partial or complete loss of its activity. Androgen insensitivity displays a broad phenotypic and genotypic spectrum. The phenotype can vary from a complete form (CAIS, complete androgen insensitivity syndrome), partial form (PAIS, partial androgen insensitivity syndrome) to a mild form (MAIS, mild androgen insensitivity syndrome). More than 400 different mutations in the androgen receptor gene have been reported. The majority of mutations are single‐base substitutions. However, deletions (1–6 base pairs), partial or complete gene deletions (>10 base pairs), insertions or duplications are also found. Mutations are compiled in the androgen receptor database (www.mcgill.ca/androgendb).

Key Concepts:

  • Androgens and the androgen receptor are indispensable for expression of the male phenotype.

  • The androgen receptor is a ligand‐dependent transcription factor and belongs to the family of nuclear receptors.

  • Despite two different ligands (testosterone and 5α‐dihydrotestosterone), only one androgen receptor cDNA has been identified and cloned.

  • A highly polymorphic (CAG)n‐CAA repeat, encoding a polyglutamine stretch, in exon 1 of the androgen receptor gene is used for identification of X‐chromosomes for carrier detection in pedigree analyses.

  • Variations in the polyglutamine stretch modulate androgen receptor transcriptional activity.

  • End‐organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS) and is distinct from other XY disorders of sex development.

  • Defects in the androgen receptor gene can prevent normal development of both internal and external male structures in 46, XY individuals.

  • End‐organ resistance to androgens is X‐linked and only 46, XY individuals are affected.

  • AR gene mutations are transmitted in an X‐linked manner, but in 30% of the cases, mutations arise de novo.

  • Androgen insensitivity can be routinely analysed and differential diagnosis is possible with other syndromes presenting with almost similar phenotypes.

Keywords: androgens; androgen receptor; androgen resistance; disorder of sex development; male sex differentiation; spinal and bulbar muscular atrophy; testicular feminisation; X‐chromosome

Figure 1.

Model of androgen action. Testosterone from the circulation diffuses through the cell membrane of an androgen target cell and can bind directly to the androgen receptor protein in the cytoplasm or after conversion to the more active metabolite 5α‐dihydrotestosterone. Hormone binding causes a conformational change, allowing nuclear entry, dimerisation with a second androgen receptor molecule and binding to specific DNA sequences, so‐called androgen responsive elements. During DNA binding of the complex, coactivator proteins are being recruited resulting in the communication with a large transcription initiation complex, containing transcription activation factors (TAFs), general transcription factors (GTFs) and RNA polymerase II. Subsequently, transcription of specific androgen responsive genes is being initiated. The newly synthesised transcripts encode specific proteins that determine the physiological response to androgens.

Figure 2.

Structural organisation of the androgen receptor and its protein. The androgen receptor gene is located on the X‐chromosome at Xq11–12 and spans more than 90 kb of DNA. The gene consists of eight coding exons. The NH2‐terminal domain is encoded by part of exon 1, the DNA‐binding domain by exons 2 and 3, whereas exons 4–7 and part of exon 8 encode the ligand‐binding domain. Exon 8 also contains the entire 3′ noncoding sequence. The androgen receptor protein contains variable polyglutamine and polyglycine stretches in the NH2‐terminal domain. The positions of the transcription activation functions (AF‐1, AF‐2, AF‐5) are indicated.

Figure 3.

Representation of the three‐dimensional (3D) structure of the androgen receptor ligand‐binding domain complexed with the synthetic androgen R1881 (methyltrienolone). Indicated are the helices 1–12‐fold in a sandwich. Each helix is coloured in a distinctive way. The numbers indicate the beginning and the end of an α‐helix, respectively. The overall structure is a globular one, allowing interactions with other proteins like coactivators and transcription factors. Copyright Dr Jian Hui Wu, the Lady Davis Institute, Molecular Modelling Laboratory, McGill University, Montreal, Canada (http://androgendb.mcgill.ca/ARmodel.jpg). Reproduced here with permission.

Figure 4.

Model representing the relative position of testosterone and amino acid residues belonging to the ligand‐binding pocket in the androgen receptor‐ligand binding domain that interacts directly with testosterone, either through Van der Waals interactions or through hydrogen bonding. Residues found to be mutated in androgen insensitivity syndrome are being coloured in red.

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Brinkmann AO and Trapman J (2000) Genetic analysis of androgen receptors in development and disease. Advances in Pharmacology 47: 317–341.

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Web Links

Androgen Receptor Gene Mutations Database World Wide Web Server. This web site contains a PDF version (downloadable) of the Database of Androgen Receptor Gene Mutations found in 46, XY individuals with the androgen insensitivity syndrome (complete syndrome, partial syndrome and mild syndrome) and also Mutations found in prostate cancer patients. The database is updated every 2 weeks and contains references to each reported mutation, as well as the type of mutation. Also a map of the mutations that cause different forms of androgen insensitivity is present http://www.mcgill.ca/androgendb/.

Androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease (AR); Locus ID: 367. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=367.

Androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease (AR); MIM number: 313700). OMIM: http://www.ncbi.nlm.nih.gov/Omim/313700.

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How to Cite close
Brinkmann, Albert O(Nov 2010) Androgen Insensitivity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006090.pub2]