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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:

http://www.indiana.edu/~ais/ 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: http://www.gfmer.ch/selected_images_v2/d etail_list.php?cat1=15&cat2=124&cat3=34 6&cat4=2&stype=n

Popular Press Article
Accomplished international runner Stripped of her medals Why?
Taken from “Punishing Difference” http://www.expressbuzz.com/edition/story.aspx?Title=Punishing+difference &artid=kunBaJO7yWk=&SectionID=f4OberbKin4=&MainSectionID=fyV9T2j Ia4A=&SectionName=cxWvYpmNp4fBHAeKn3LcnQ==&SEO=gender,%20 sexualities,%20santhi%20soundararajan

Santhi Soundararajan
I can’t walk! Well, you have legs.

Androgen Receptor
First linked to AIS in mice

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

AR Motifs
Using MOTIF

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?

Homology
Identities
Chimpanzee Rat 0.73 0.84

Expect
6E-50 0

Mouse
Dog Cattle

0.84
0.87 0.79

0
0 2E-171

Zebra fish
Chicken

0.67
0.58

2E-161
0

Homology

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

Homology

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

Phylogeny
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
UBE2I CCND1 HTATIP BRCA1 BAG1 NCOA1 NCOA2 RNF14 TGFB1I1 NCOA4

Those highlighted are protooncogenes.

Drugs interacting with AR
Flutamide Nilutamide Oxandrolone Testosterone Dromostanolone Cyproterone

Bicalutamide
Finasteride

Nandrolone
Fluoxymesterone

Conclusions
• 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

Questions?

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

References
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: http://hormones.gr/preview.php?c_id=227 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: http://jcem.endojournals.org/cgi/content/abstract/85/8/2664 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: http://www.hawaii.edu/PCSS/online_artcls/intersex/AndrogenInsensitivity.htm 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: http://www.jstor.org/stable/35117?seq=1 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

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