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AIS (Androgen Insensitivity Syndrome) and the androgen receptor (AR

Sam Trammell

AIS and AR outline
• What is Androgen Insensitivity Syndrome? • How is the androgen receptor linked to AIS? • What accounts for the variability in the syndrome? • Are there AR homologs in other species? • What genes are interacting with AR? • What compounds interact with the receptor?

Androgen Insensitivity Syndrome (AIS)
Androgen=testosterone Usually, modified to dihydrotestosterone in the cytoplasm Insensitive=“never calls back”

Put the two together and you get the idea

Androgen Insensitivity Syndrome (AIS)
Take it away
•Alias: Testicular Feminization •Prevalence: 1 in 20,000 births •Most prevalent form of intersexism •XY karyotype •Possibly feminized features •Ambiguous or undeveloped genitalia
Two individuals with AIS

AISSG-USA Support Group Retrieved from: html/ais_facts.html

Androgen Insensitivity Syndrome (AIS)
Hermaphrodite ≠ Intersex Not necessarily associated with homosexuality

Androgen Insensitivity Syndrome (AIS)
Mild AIS (MAIS), Partial AIS (PAIS), Complete AIS (CAIS) All images from: Geneva Foundation for Medical Education and Research Retrieved from: etail_list.php?cat1=15&cat2=124&cat3=34 6&cat4=2&stype=n

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Androgen Receptor
First linked to AIS in mice

Homolog found in humans
Those with CAIS found to have a mutation in AR

AR Motifs

Sex-determining Y gene product region Expected!

Others were unrelated or insignificant to AIS

Protein Domains
Gene encodes 920 amino acid protein Using SMART 3 Domains

Steroid or nuclear hormone receptor (NR)

Zinc Finger

Ligand binding

Protein Domains
Androgen receptor N-terminus, DNA binding, ligand binding Zinc finger DNA binding, dimerizes upon activation Ligand Binds ligand, for us DHT (dihydrotestosterone)

Protein Domain
Function • Androgen receptor responds to androgen in cytoplasm • Conformational change increases affinity for ligand in ligand domain • Protein binds DNA to initiate transcription of other genes Accounts for phenotypic variance?

Chimpanzee Rat 0.73 0.84

6E-50 0

Dog Cattle

0.87 0.79

0 2E-171

Zebra fish




X-axis: Human AR Y-axis: Predicted similar gene to human AR in chimpanzees


X-axis: Human AR Y-axis: Predicted similar gene to human AR in cattle

Homolog in C. elegans
Using Wormbase nhr-69 nuclear hormone receptor-69 • Does not determine sex, but mutations in it can lead to both maternal and offspring infertility
– Acts to develop germline

Would not use as a model organism for AIS

Aligned with T-Coffee

Gene Ontology (using GO Consortium)
Biological processes: Cellular Component: • • • • • • • Cell growth Cytoplasm Prostate gland Nucleus development Cell to cell signaling Signal transduction Sex determination Molecular processes: • Androgen receptor activity • Transcription activity • DNA binding

Protein Interactions
Using String

Protein Interactions

Those highlighted are protooncogenes.

Drugs interacting with AR
Flutamide Nilutamide Oxandrolone Testosterone Dromostanolone Cyproterone



• Mutations in androgen receptor cause AIS
– Severity depends on mutation location in domain and mutation type (nonsynonymous or synonymous or nonsense)

Androgen receptor accounts for many trait differences in males and females
– Determines gonad type – Puberty – Regulates body and pubic hair growth

Androgen receptor is highly conserved in mammals and higher organisms but does not have a direct homolog in more distantly related organisms
– Should not be used a to determine speciation events, example, chimpanzee and cattle

Regulates cell division
– Target for anti-cancer drugs

Future Directions
• Search for more interacting genes
– RNAi screen – Chemical genetics

• Does the androgen receptor play an important role in upregulating genes and/or silencing genes during puberty?
– Microarrays!
• Current microarray studies focus on differential gene expression on the body


Thank you
A special thank you to Ahna Skop for all of her help and guidance.

1. 2. Galani, A., Kitsiou-Tzeli, S., Sofokleous, C., Kanavakis, E., Kalpini-Mavrou, A. (2008). Androgen insensitivity syndrome: clinical features and molecular defects. HORMONES 7(3). Retrieved from: Wisniewski, A., Migeon, C., Meyer-Bahlburg, H., Gearhart, J., Berkovitz, G., Brown, T., Money, J. (2000). Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome. Clinical Endocrinology and Metabolism 85(8). Retrieved from: Hines, M., Ahmed, S., Hughes, I. (2003). Psychological Outcomes and Gender-Related Development in Complete Androgen Insensitivity Syndrome. Archives of Sexual Behaviors 32(2). doi: 10.1023/A:1022492106974 Diamond, M., Watson, L. A. (2004). Androgen insensitivity and Klinefelter's syndrome: sex and gender considerations. Child Adolesc Psychiatric Clin N. Arm. of North America 13. Retrieved from: Lubahn, D., Brown, T., Simental, J., Higgs, H., Migeon, C., Wilson, E., French, F. (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 syndrome. Proc. Natl. Acad. Sci 86. Retrieved from: Holterhus, P., Hiort, O., Demeter, J., Brown, P., Brooks, J. (2003). Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor. Genome Biology 4(R37). Doi: 10.1186/gb-2003-4-6-r37

3. 4. 5.