Androgen Insensitivity

Abstract

Androgen insensitivity is an X‐linked disorder of defective or absent virilisation in 46, XY individuals owing to complete or partial resistance to androgens in androgen‐dependent tissues and organs. The syndrome is part of a group of disorders of sex development (DSD). The molecular cause of the syndrome is mutations in the androgen receptor gene (locus: Xq11–12), resulting either in the absence of an androgen receptor protein or in the production of a mutant receptor with partial or complete loss of its activity. Androgen insensitivity displays a broad phenotypic and genotypic spectrum. The phenotype can vary from complete (CAIS, complete androgen insensitivity syndrome), partial (PAIS, partial androgen insensitivity syndrome) to mild (MAIS, mild androgen insensitivity syndrome). More than 450 different mutations in the androgen receptor gene have been reported. The majority of mutations are single‐base substitutions. However, deletions (1–6 bp), partial or complete gene deletions (>10 bp), insertions or duplications are also found.

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 the 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.
  • A number of cases of AIS present with no identifiable mutation in the androgen receptor, which has been estimated at between 25% and 33% of individuals presenting with androgen resistance.

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 N/C‐terminal interactions, 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, coregulatory proteins are recruited resulting in the communication with a large transcription initiation complex, containing transcription activation factors, general transcription factors and RNA polymerase II. Subsequently, transcription of specific androgen responsive genes is initiated. The newly synthesised transcripts encode specific proteins that determine the physiological response to androgens.
Figure 2. Structural organisation of the androgen receptor gene and its protein. The androgen receptor gene is located on the X‐chromosome at Xq11–12 and spans almost 190 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 (untranslated region). The androgen receptor protein contains variable polyglutamine (Q) and polyglycine (G) stretches in the NH2‐terminal domain. Current numbering uses the NCBI reference sequence NM_000044.3: 920 amino acids with poly‐Q and poly‐G repeats of 23 residues. The positions of the transcription activation functions (AF‐1, AF‐2) are indicated along with the 3D structures for the isolated LBD (1I37) and DBD (1R4I).
Figure 3. Representation of the three‐dimensional (3D) structure of the androgen receptor ligand‐binding domain complexed with DHT and an LxxLL peptide (a). (b) Structure of the homodimer interface with the UBA3 (LxxLL) peptide (5JJM) (Nadal et al., ). The overall structure is a highly α‐helical globular one (numbering of helices indicated), allowing interactions with other proteins such as coactivators and transcription factors (AF2 pocket).
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, or DHT, either through Van der Waals interactions or through hydrogen bonding (N706, Q712, R753, T878). Residues found to be mutated in androgen insensitivity syndrome are coloured in orange.
close

References

Berrevoets CA, Doesburg P, Steketee K, Trapman J and Brinkmann AO (1998) Functional interactions of the AF‐2 activation domain core region of the human androgen receptor with the amino‐terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor 2). Molecular Endocrinology 12: 1172–1183.

Boehmer AL, Brinkmann AO, Niermeijer MF, et al. (1997) Germ‐line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling. American Journal of Human Genetics 60: 1003–1006.

Boehmer ALM, Brinkmann AO, Brüggenwirth HT, et al. (2001) Genotype versus phenotype in families with androgen insensitivity syndrome. Journal of Clinical Endocrinology and Metabolism 86: 4151–4160.

Brown CJ, Goss SJ, Lubahn DB, et al. (1989) Androgen receptor locus on the human X chromosome: regional localization to Xq11–12 and description of a DNA polymorphism. American Journal of Human Genetics 44: 264–269.

Cato L, Neeb A, Sharp A, et al. (2017) Development of Bag‐1L as a therapeutic target in androgen receptor‐dependent prostate cancer. Elife 6: e27159.

Centenera MM, Harris JM, Tilley WD and Butler LM (2008) The contribution of different androgen receptor domains to receptor dimerization and signaling. Molecular Endocrinology 22: 2373–2382.

Chang CS, Kokontis J and Liao ST (1988) Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240: 324–326.

Christiaens V, Bevan CL, Callewaert L, et al. (2002) Characterization of the two coactivator‐interacting surfaces of the androgen receptor and their relative role in transcriptional control. Journal of Biological Chemistry 277 (51): 49230–49237.

Crocoll A, Zhu CC, Cato AC and Blum M (1998) Expression of androgen receptor mRNA during mouse embryogenesis. Mechanisms of Development 72 (1–2): 175–178.

De Mol E, Fenwick RB, Phang CT, et al. (2016) EPI‐001, a compound active against castration‐resistant prostate cancer, targets transactivation unit 5 of the androgen receptor. ACS Chemical Biology 11 (9): 2499–2505.

De Mol E, Szulc E, Di Sanza C, et al. (2018) Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators. Structure 26 (1): 145–152.

Deeb A, Mason C, Lee YS and Hughes IA (2005) Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clinical Endocrinology (Oxford) 63: 56–62.

Dehm SM, Schmidt LJ, Heemers HV, Vessella RL and Tindall DJ (2008) Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Research 68 (13): 5469–5477.

Doesburg P, Kuil CW, Berrevoets CA, et al. (1997) Functional in vivo interaction between the amino‐terminal, transactivation domain and the ligand binding domain of the androgen receptor. Biochemistry 36: 1052–1064.

Estebanez‐Perpina E, Arnold LA, Nguyen P, et al. (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proceedings of the National Academy of Sciences of the United States of America 104: 16074–16079.

Geissler WM, Davis DL, Wu L, et al. (1994) Male pseudohermaphroditism caused by mutations of testicular 17 beta‐hydroxysteroid dehydrogenase 3. Nature Genetics 7: 34–39.

George FW and Wilson JD (1994) Sex determination and differentiation. In: Knobil E and Neill JD (eds) The Physiology of Reproduction, 2nd edn, pp. 3–28. New York, NY: Raven Press.

Gottlieb B, Beitel LK, Nadarajah A, Paliouras M and Trifiro MA (2012) The androgen receptor gene mutations database (ARDB): 2012 update. Human Mutation 33: 887–894.

Grino PB, Griffin JE and Wilson JD (1990) Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology 126: 1165–1172.

Haelens A, Tanner T, Denayer S, Callewaert L and Claessens F (2007) The hinge region regulates DNA binding, nuclear translocation, and transactivation of the androgen receptor. Cancer Research 67 (9): 4514–4523.

Hay CW and McEwan IJ (2012) The impact of point mutations in the human androgen receptor: classification of mutations on the basis of transcriptional activity. PLoS One 7 (3): e32514.

He B, Kemppainen JA and Wilson EM (2000) FXXLF and WXXLF sequences mediate the NH2‐terminal interaction with the ligand binding domain of the androgen receptor. Journal of Biological Chemistry 275: 22986–22994.

He B, Bai S, Hnat AT, et al. (2004) An androgen receptor NH2‐terminal conserved motif interacts with the COOH terminus of the Hsp70‐interacting protein (CHIP). Journal of Biological Chemistry 279 (29): 30643–30653.

Holterhus PM, Brüggenwirth HT, Brinkmann AO and Hiort O (2001) Post‐zygotic mutations and somatic mosaicism in androgen insensitivity syndrome. Trends in Genetics 17: 627–628.

Hornig NC, de Beaufort C, Denzer F, et al. (2016) A recurrent germline mutation in the 5′UTR of the androgen receptor causes complete androgen insensitivity by activating aberrant uORF translation. PLoS One 11: e0154158.

Hu R, Lu C, Mostaghel EA, et al. (2012) Distinct transcriptional programs mediated by the ligand‐dependent full‐length androgen receptor and its splice variants in castration‐resistant prostate cancer. Cancer Research 72 (14): 3457–3462.

Hughes IA (2008) Disorders of sex development: a new definition and classification. Best Practice & Research. Clinical Endocrinology & Metabolism 22: 119–134.

Hunter I, Hay CW, Esswein B, Watt K and McEwan IJ (2018) Tissue control of androgen action: The ups and downs of androgen receptor expression. Molecular and Cellular Endocrinology 465: 27–35.

Jakob M, Kolodziejczyk R, Orlowski M, et al. (2007) Novel DNA‐binding element within the C‐terminal extension of the nuclear receptor DNA‐binding domain. Nucleic Acids Research 35: 2705–2718.

Jenster G, van der Korput HA, van Vroonhoven C, et al. (1991) Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Molecular Endocrinology 5: 1396–1404.

Jenster G, de Ruiter PE, van der Korput HA, et al. (1994) Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine‐stretch variation, and mutation of putative phosphorylation sites. Biochemistry 33: 14064–14072.

Jenster G, van der Korput HA, Trapman J and Brinkmann AO (1995) Identification of two transcription activation units in the N‐terminal domain of the human androgen receptor. Journal of Biological Chemistry 270: 7341–7346.

Jones D, Wade M, Nakjang S, et al. (2015) FOXA1 regulates androgen receptor variant activity in models of castrate‐resistant prostate cancer. Oncotarget 6 (30): 29782–29794.

Kazemi‐Esfarjani P, Trifiro MA and Pinsky L (1995) Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n‐expanded neuronopathies. Human Molecular Genetics 4: 523–527.

Kohler B, Lumbroso S, Leger J, et al. (2005) Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. Journal of Clinical Endocrinology and Metabolism 90: 106–111.

Kuiper GG, Faber PW, van Rooij HC, et al. (1989) Structural organization of the human androgen receptor gene. Journal of Molecular Endocrinology 2: R1–R4.

Langley E, Zhou ZX and Wilson EM (1995) Evidence for an anti‐parallel orientation of the ligand‐activated human androgen receptor dimer. Journal of Biological Chemistry 270: 29983–29990.

La Spada AR, Wilson EM, Lubahn DB, Harding AE and Fischbeck KH (1991) Androgen receptor gene mutations in X‐linked spinal and bulbar muscular atrophy. Nature 352: 77–79.

Lavery DN and McEwan IJ (2008) Structural characterization of the native NH2‐terminal transactivation domain of the human androgen receptor: a collapsed disordered conformation underlies structural plasticity and protein‐induced folding. Biochemistry 47: 3360–3369.

Li SL, Ting SS, Lindeman R, Ffrench R and Ziegler JB (1998) Carrier identification in X‐linked immunodeficiency diseases. Journal of Paediatrics and Child Health 34: 273–279.

Li W, Cavasotto CN, Cardozo T, et al. (2005) Androgen receptor mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant ART‐27 coactivator function. Molecular Endocrinology 19 (9): 2273–2282.

Lubahn DB, Joseph DR, Sullivan PM, et al. (1988) Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240: 327–330.

Lubahn DB, Brown TR, Simental JA, et al. (1989) Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proceedings of the National Academy of Sciences of the Unite States of America 86: 9534–9538.

Matias PM, Donner P, Coelho R, et al. (2000) Structural evidence for ligand specificity in the binding domain of the human androgen receptor: implications for pathogenic gene mutations. Journal of Biological Chemistry 275: 26164–26171.

McEwan IJ (2012) Intrinsic disorder in the androgen receptor: identification, characterisation and drugability. Molecular BioSystems 8 (1): 82–90.

Mongan NP, Tadokoro‐Cuccaro R, Bunch T and Hughes IA (2015) Androgen insensitivity syndrome. Best Practice & Research Clinical Endocrinology & Metabolism 29 (4): 569–580.

Nadal M, Prekovic S, Gallastegui N, et al. (2017) Structure of the homodimeric androgen receptor ligand‐binding domain. Nature Communications 8: 14388.

Pereira de Jesus‐Tran K, Cote PL, Cantin L, et al. (2006) Comparison of crystal structures of human androgen receptor ligand‐binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Science 15: 987–999.

Poujol N, Wurz JM, Tahiri B, Lumbroso S, et al. (2000) Specific recognition of androgens by their nuclear receptor: a structure–function study. Journal of Biological Chemistry 275: 24022–24031.

Quigley CA, De Bellis A, Marschke KB, et al. (1995) Androgen receptor defects: historical, clinical and molecular perspectives. Endocrine Reviews 16: 271–321.

Reid J, Kelly SM, Watt K, Price NC and McEwan IJ (2002) Conformational analysis of the androgen receptor amino‐terminal domain involved in transactivation: influence of structure‐stabilizing solutes and protein–protein interactions. Journal of Biological Chemistry 277 (22): 20079–20086.

Sack JS, Kish KF, Wang C, et al. (2001) Crystallographic structures of the ligand‐binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proceedings of the National Academy of Sciences of the United States of America 98: 4904–4909.

Shaffer PL, Jivan A, Dollins DE, Claessens F and Gewirth DT (2004) Structural basis of androgen receptor binding to selective androgen response elements. Proceedings of the National Academy of Sciences of the United States of America 101: 4758–4763.

Steketee K, Berrevoets CA, Dubbink HJ, et al. (2002) Amino acids 3–13 and amino acids in and flanking the 23FxxLF27 motif modulate the interaction between the N‐terminal and ligand‐binding domain of the androgen receptor. European Journal of Biochemistry 269: 5780–5791.

Tadokoro R, Bunch T, Schwabe JW, Hughes IA and Murphy JC (2009) Comparison of the molecular consequences of different mutations at residue 754 and 690 of the androgen receptor (AR) and androgen insensitivity syndrome (AIS) phenotype. Clinical Endocrinology (Oxford) 71: 253–260.

Tadokoro‐Cuccaro R, Davies J, Mongan NP, et al. (2014) Promoter‐dependent activity on androgen receptor N‐terminal domain mutations in androgen insensitivity syndrome. Sexual Development 8 (6): 339–349.

Tilley WD, Marcelli M, Wilson JD and McPhaul MJ (1989) Characterization and expression of a cDNA encoding the human androgen receptor. Proceedings of the National Academy of Sciences of the United States of America 86: 327–331.

Trapman J, Klaassen P, Kuiper GG, et al. (1988) Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochemical and Biophysical Research Communications 153: 241–248.

Van Laar JH, Bolt‐de Vries J, Voorhorst‐Ogink MM and Brinkmann AO (1989) The human androgen receptor is a 110 kDa protein. Molecular and Cellular Endocrinology 63: 39–44.

Wilson JD, Harrod MJ, Goldstein JL, Hemsell DL and MacDonald PC (1974) Familial incomplete male pseudohermaphroditism, type 1. Evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome. New England Journal of Medicine 290: 1097–1103.

Wilson JD, Griffin JE and Russell DW (1993) Steroid 5 α‐reductase 2 deficiency. Endocrine Reviews 14: 577–593.

Zhou ZX, Lane MV, Kemppainen JA, French FS and Wilson EM (1995) Specificity of ligand‐dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Molecular Endocrinology 9: 208–218.

Further Reading

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

Enmark E and Gustafsson JA (1996) Orphan nuclear receptors – the first eight years. Molecular Endocrinology 10: 1293–1307.

Evans R (1988) The steroid and thyroid hormone receptor superfamily. Science 240: 889–894.

Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM and Kruse K (1998) Inherited and de novo androgen receptor gene mutations: investigation of single‐case families. Journal of Pediatrics 132: 939–943.

Orafidiya FA and McEwan IJ (2015) Trinucleotide repeats and protein folding and disease: the perspective from studies with the androgen receptor. Future Science OA 1 (2): FSO47.

Pinsky L, Trifiro M, Kaufman M, et al. (1992) Androgen resistance due to mutation of the androgen receptor. Clinical and Investigative Medicine 15: 456–472.

Ris‐Stalpers C, Hoogenboezem T, Sleddens HFBM, et al. (1994) A practical approach to the detection of androgen receptor gene mutations and pedigree analysis in families with X‐linked androgen insensitivity. Pediatric Research 36: 227–234.

Robinson‐Rechavi M, Carpentier AS, Duffraisse M and Laudet V (2001) How many nuclear hormone receptors are there in the human genome? Trends in Genetics 17: 554–556.

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://androgendb.mcgill.ca/

Androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease (AR); https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=367.

Androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease (AR); gene card. http://www.genecards.org/cgi‐bin/carddisp.pl?gene=AR&keywords=androgen,receptor.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
McEwan, Iain J(Jul 2018) Androgen Insensitivity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006090.pub3]