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von Hippel-Lindau Syndrome (VHL)

von Hippel-Lindau Syndrome (VHL). Justin Melton. von Hippel-Lindau Syndrome. Multi-system disorder characterized by abnormal growth of blood vessels. VHL the gene. Tumor suppressor gene Inherited in an Autosomal Dominant fashion Mapped to chromosome 3p25-26 using genetic linkage analysis

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von Hippel-Lindau Syndrome (VHL)

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  1. von Hippel-Lindau Syndrome (VHL) Justin Melton

  2. von Hippel-Lindau Syndrome • Multi-system disorder characterized by abnormal growth of blood vessels

  3. VHL the gene • Tumor suppressor gene • Inherited in an Autosomal Dominant fashion • Mapped to chromosome 3p25-26 using genetic linkage analysis • Has 3 exons encoding 4.7 kb mRNA • Highly conserved sequence in rodents and primates • Homologs in C. elegans and Drosphila

  4. pVHL the protein • 213 amino acid protein • Has 2 main binding or active sites (alpha and beta) • Alpha site binds to an E3 ligase • Beta site binds to HIF-1α – a transcription factor

  5. Inheritance

  6. Review:

  7. Normal VHL Function

  8. Normal fuction important? Uh… YEAH!

  9. HIF transcription factor

  10. Knockout Mice • Vhl-/- mice die in utero at day 10.5-12.5. • Vhl+/- are phenotypically normal and show no signs of disease until up to 15 months.

  11. So what if we lose it in humans?

  12. Mutations Cont.

  13. VHL in Cancer

  14. Future

  15. Treatments? • Usual cancer treatments: chemotherapy, cryotherapy, radiation and surgery. • Hundreds of clinical trials currently taking place involving VHL in some fashion. • Some target VHL specifically while others target downstream events, such as TGFβ transcription.

  16. Sources • http://www.vhl.org • Kim, William and Kaelin, William Jr. “The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer.” Current Opinion 2003 13: pp55-60. • Richards, Frances. “Molecular Pathology of von Hippel-Lindau disease and the VHL tumor suppressor gene.” Exp. Rev. Mol. Med. 19 March 2001. • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.143 • http://www.clinicaltrials.gov

  17. Questions?

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