5 alpha reductase and its role in male pattern baldness
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Transcript of 5 alpha reductase and its role in male pattern baldness
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5 alpha reductase and its role in male pattern
baldnessBy Chris Stewart
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The Disease
-“an impairment of health or a condition of abnormal functioning”
What about androgenic alopecia?
Very high prevalence-50% over age 50….
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How it happens
http://www.surviving-hairloss.com/DHT.html
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How it’s classified
Norwood, O'tar T. (1975) Male Pattern Baldness: classification and Incidence. Southern medical journal, 68(11):1359-1365
Hamilton-Norwood scale
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Why is it such a big deal?
• Loss of control• Loss of individuality, ability to express oneself• Sign of weakness• Unattractive
http://www.superstock.com/stock-photos-images/1439R-108011
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Historically
• Scalping as a sign of prowess, trophy of war• In the military-removes external signs of
individuality• Neo-Nazis• Monks as a sign of commitment• Express individuality
http://www.dailymail.co.uk/news/article-518499/Buddhist-monk-cut-pieces-run-lawnmower-Milton-Keynes-temple.html
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Treatments• All drugs were originally designed for
something else-Minoxidil(Rogaine): Originally for high blood pressure
-Finasteride(Proscar):Specific to SRD5A2-Dutasteride(Avodart):Non-Specific
Camille DeClementi; Keith L. Bailey, Spencer C. Goldstein, and Michael Scott Orser (December 2004). "Suspected
toxicosis after topical administration of minoxidil in 2 cats". Journal of Veterinary Emergency and Critical Care 14 (4): 287–292. doi:10.1111/j.1476-4431.2004.04014.x
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TTTCTGCTCTGGGAAGGAAAGACAGGAAAGAGACCAAGGGATGTTAGGGTTCAGAGAAAGACTGTCCAGCCTCAGTAAAGTCTCACAGGGAAAGGGAAGAACGAACACATGTTAAATTGCCTACCATGCCCAATCGTTTAGTATCTATGGTCTCACTTAACTCTGTTGTAACCTTTTGAGAGATATTTATTATGTCCACTTTACAAAGAAACTGAGGCTGAGTAAGGTTATGGGACTGAAAGAAGACAATACAGCTGGTGCCCGCTAAGATGCAAATCTGAGCTTGTGAATCTCTGAGGTTTAAGACCTTTTAGCCGTTTTAAGTAGGCAGATATTCTATGCAAGAAGAGAACAGAGCCCATAAACAGAGAAAAGTTATCAAACGAAATCAAAACCTTGAAGGTTTTGCCTTATTTTGAGTAGAAGATTCCTAGGGTCAAAAGATCAAGGAAGTTTGGATTAGAAATTAGGATAAAGAATGCCTCTGGCATAATCTGTCTCGTAAAGAGAAAGTGATGCCTCATTTCGAGAGAAGAAGGTGTCAGAGACGGATTTCAAACTGTCTTTCTTAATTTCCTCTTATCCTCTGAATCTTCTTTATTGGTCAAGATTTAATATTTATGCAATCTTAACTGAATTCTCACTCTTTTTAAAAGGCAAATGTTGTCAAGTAATAAGAACTAAACTGTATCCTTTCAACAAATATTTACTAAAAGCCTGCTGTGAACAAGATTCTTTATTTTACACAGATTTTATTTTACTCAGATTTAGATGGTTTAATTTGCACAGAAAGAAGGATGTTGGATACAGGAGATAAGAGATTAGTTTTTTATTTCACTGATTTTTGAACAGACATTTGACAGAAATGTGATTTTTGTCAACAATTATTTTTATCTTCAAATTAACTACTGTATGTTGGCAACATAAGCAATATTTTTATGAGGTCATTTCATCTTAATGATTAGTGTTTTGTGACAATCATATTAATGTAATCTTTAGGCTTGTTTTTGAAATCAAAAGGCACTTTGCACAATACATTATGACCGGTGCATTTAAAAAAAAACCCAAAGGAGTAATTATGCATAAAACAAATATCTACATATTGTCCTTCTTCAGAGGAAATTTTAAAATATTAGTAAAGGACTTGGAGATTCATTCTGCCTGAGGGAAAATTGCCCACTGGAAGTACAACTCTTGAGCTACTTGTTCCTGAGGCATCGGGATCTGATGTTTGTCTTTCCTCTTTTTTGAATTCTTTCTTTGAAGCCACTGGAGTGTGTGATCTGTTATTATTTGAGTGCTTACAGGGTGTTACACTCTGTGTGCCAAACACTCTGAGTTAATAATTTACTCATCCTCATACCAACCCATTTAGGTAGGCACGCCCATTTTGCAGGTGGAAAACTGGAGCAAGAAAAGGTTAAATAACTTCCTTGCCCAAGGTCACACAATAACGAGGAATCAGAGTTCAAACCCAGGCAGTAGACTCCAGATCTCAGGCTCTTCAGGTATGATAATAAACTGTTGTATACTTGTTGGATAAATGCGACCTCATTCTTGCTTTTTAAAAACTATATTTATTCTTAAAATTATTATGTAAAAATTTTTTAAATTATAAAAACATTTTTTCCTAATGAAAAATGGAAAAATCCCAAAAGTAGAAAATACTCATAATTACATCTAAGTATATTAAATATTAATGTTTTAGAGAATTTCTATCAAATCTTTTTCCTTAGTAGATTTTCACACATGCTTGTTATGTTGAATATATGGTTTTTTAGTTCTGTTTAATTACCTAACATTTTATAGTATTTTCCAACATTATCACAGATTTCTTAATATCTGCTTATTTCATCTACTGTAAAAATAATAATTTACCTATATATTCATTTATAGTTGGACATTTAATTTGTCTTGGGGTGAGGCTAGGTTCATTGAAGCTGTGATGTACATTTTTTGCATCTAAATTCTTTTCAAAGGTTAGATCTATTTTCTTAGGATTTCCAGAAGTGGTTCAAAGGTTATGAACATTCTTTAGGGTCTTGATATAATCATACATATCTGTTTCGAGGCTTAAGGAGTCATTTGGCTTGATACTGAGGGTGCATTAAGGAACAAGCATCAGGCTGTCTTGGCTTTATCTCGTGCTGTGTGTTGCTAAGACAGAGAATAAGACGGAGAGACAGGGAGAAAGGATGGCTCAGGTTTGGCTCAGACTCTTTTGCAAAATGTCCATTGGGGACTGTTCAAAGCAGCAATATGTCCCATCAAATAGAAGTTAAAACTCATTGTACTTTTCTCAATACAAGGATGGCACACAAGAATGTAGATTCCACAGGGTCAAAGGTTTTTGTCTCACTTTTATGGCTGTATCCCCATTGTATACAAAGAGCTGGTACATAGTTGGTACTCACTAGAATTTGTTGAATGCATGAATGAACTCTACTTACAACAACCGTACAGACAGAATTGTAGGAGAGCTAGCAATTACTTGGGAATCATAATTGCTGAGATTGCATAGTTAGGTCAATTCAGATAACTTTCCTCTCTTCAGAATCTATTGTTGTGGCTGTTTGGATTCTTTAGCCACATGGAAATGACTGCTGCCTAAGCACATTGCCTAATCCCACTGCCAAAGGCATTTGAAGTCAAGAGTTATCTCACCTCTTTTTTTTTTTTTTTTTTTTAATGTTTTTTTTTTTATTATACTCTAAGTTTTAGGGTACATGTGCACATTGTGCAGGTTAGTTACATATGTATACATGTGCCATGCTGGTGCGCTGCACCCACTAACGTGTCATCTAGCATTAGGTATATCTCCCAATGCTATAAGAAAAACCAACACAGAGACCACCACAGTTCCCAGAGTGTGATATTCCCCTTCCTGTGTCCATGTGATCTCATTGTTCAATTCCCACCTATGAGTGAGAATATGCGGTGTTTGGTTTTTTGTTCTTGCGATAGTTTACTGAGAATGATGGTTTCCAATTTCATCCATGTCCCTACAAAGGACATGAACTCATCATTTTTTATGGCTGCATAGTATTCCATGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATTGTTGGACATTTGGGTTGGTTCCAAGTCTTTGCTATTGTGAATAGTGCCACAATAAACATATGTGTGCATGTGTCTTTATAGCAGCATGATTTATAGTCCTTTGGGTATATACCCAGTATTGGGATGGCTGGGTCAAATGGTATTTCTAGTTCTAGATCCCTGAGGAATCGCCACACTGACTTCCAC
The Gene
3-oxo-5 alpha-steroid 4-dehydrogenase 2 or SRD5A2
Type 2 isoform:• 58,587 b.p. on chromosome 2• Accession#:NC_000002.10/GI:89161199• 50% homologous with type 1 isoformhttp://www.genecards.org/cgi-bin/carddisp.pl?gene=SRD5A2&search=SRD5A2
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MotifsWKVnRRRnVWK• W=A/T, K=G/T, V=G/A/C, and R is a
purine(A/G)
Highly mutated in prostate cancer
Named “Themis” after the Greek goddess of prophecy.
Markridakis, N.M., Caldas Ferraz, L.F., and Reichardt, J.K. 2009. Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. Hum Mutat. 30(1):39-48
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The Protein
• 254 Amino Acids• Accession #: NP_000339.2/GI:39812447• Active at a slightly acidic pH
http://pfam.sanger.ac.uk/clan?id=Steroid_dh
http://www.expasy.ch/cgi-bin/prosite/sequence_logo.cgi?ac=PS50244
http://smart.embl-heidelberg.de/smart/show_motifs.pl
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Structure
TMHMM predicted 6 transmembrane helices-
-37%
hydrophobichttp://www.cbs.dtu.dk/services/TMHMM/
GO:0016021=Integral to cell membrane
http://amigo.geneontology.org/cgi-bin/amigo/gp-assoc.cgi?gp=UniProtKB:P31213&session_id=8271amigo1240360044
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http://www.treefam.org/cgi-bin/treeview.pl?ac=TF314668&stype=clean&misc=aln&highlight=SRD5A2_HUMAN
SRD5A1
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Function
-Conversion of testosterone to dihydrotestosterone(DHT)-Knockout leads to male pseduohermaphroditism
http://www.brenda-enzymes.org/php/result_flat.php4?ecno=1.3.99.5
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Function in Plants-DET-2 gene homolog in Arabidopsis-Essential in Brassinosteroid synthesis
Li, J., Biswas, M.G., Chao, A., Russell, D.W., and Chory, J. (1997) Conservation of function between mammalian and plant steroid 5 alpha reductases. Proc. Natl. Acad. Sci. 94:3554-3559
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InteractionsAro: Aromatase
HSD: hydroxy-steroid dehydrogenase
UGT:UDP- glucuronosyltransferase
http://string.embl.de/newstring_cgi/show_network_section.pl
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http://www.endotext.org/Pediatrics/pediatrics7/pediatrics7.html
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UDP- glucuronosyltransferase (UGT)
-Addition of glucuronic acid alters solubility
-Assists excretion of toxins, drugs, hormones, etc..
-Did you know?
http://www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/c14.html
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Do you think your outlook on life would change if you found out you
were going to be bald in the future?
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Genetic Testing-250$ for a cheek swab-Test for Androgen receptor variant
Also available for women-Based on CAG repeat score
http://www.hairdx.com/
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Current Pursuits
• Wnt signalling in abrasions– Cells return to embryonic responsive stateIto, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. 2007.
Nature. 447:316-320, doi:10.1038/nature05766
• Hair CloningCooley, J. Follicular cell implantation: an update on “hair follicle cloning” 2004. Facial Plastic Surgery Clinics of North America. 12:2(219-224), doi:10.1016/j.fsc.2004.01.003