Transcript AIS: Androgen Insensitivity Disorder

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
Santhi
Soundararajan
I can’t walk!
Well, you have
legs.
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
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
Expect
Chimpanzee
0.73
6E-50
Rat
0.84
0
Mouse
0.84
0
Dog
0.87
0
Cattle
0.79
2E-171
Zebra fish
0.67
2E-161
Chicken
0.58
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:
Molecular processes:
•
••
•
•
•
•
• Androgen receptor
activity
• Transcription activity
• DNA binding
Cell growth
Cytoplasm
Prostate gland
Nucleus
development
Cell to cell signaling
Signal transduction
Sex determination
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
Oxandrolone
Dromostanolone
Nilutamide
Testosterone
Cyproterone
Bicalutamide
Nandrolone
Finasteride
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
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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