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Tuberous Sclerosis TSC2

Tuberous Sclerosis TSC2. Morgan von Drehle. Tuberous Sclerosis. Autosomal dominant disorder Sporadic mutations in ~ 2 / 3 cases Occurs in ~1 out of 6,000 individuals Affects organs: brain, heart, kidneys, eyes, skin, lungs Hamartomas Disorder of cell proliferation and migration.

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Tuberous Sclerosis TSC2

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  1. Tuberous Sclerosis TSC2 Morgan von Drehle

  2. Tuberous Sclerosis • Autosomal dominant disorder • Sporadic mutations in ~ 2 / 3 cases • Occurs in ~1 out of 6,000 individuals • Affects organs: brain, heart, kidneys, eyes, skin, lungs • Hamartomas • Disorder of cell proliferation and migration

  3. Major Features • Neurological disorder • Tubers, fibromas, hamartomas • Discoloration of skin patches http://www.emedicine.com/neuro/topic386.htm

  4. Minor Features • Rectal polyps • Cysts • Ginigival fibromas • Skin lesions http://www.emedicine.com/neuro/topic386.htm

  5. TSC2 • tumor suppressor gene • on chromosome 16p13.3 • 43kb genomic DNA • Regulates cell growth, proliferation, differentiation, and migration http://biology.kenyon.edu/slonc/bio38/howell/tsc.htm

  6. Tuberin • Protein product of TSC2 • 200kD protein • 7 functional domains • Forms Tuberin Sclerosis Complex with TSC1 Goncharova et al.

  7. mTOR pathway http://www.biocarta.com/pathfiles/h_mTORPathway.asp

  8. mTOR pathway simplified

  9. Experiments: Drosophila

  10. Experiments: Transgenic Rats Momose et al.

  11. Mutations in TSC2 • Splice site mutations • Deletions • Insertions • Missense mutations • Nonsense mutations Nellist et al.

  12. Single Amino Acid Change COS Cells Nellist et al.

  13. Treatments • Rapamycin treatment (in mice): • Predicted short-term clinical efficacy • Unclear of optimal dosing schedule, duration of response, and potential rapamycin resistance Yeung, R. / Lee et al.

  14. References • Momose, S., Kobayashi, T., Mitani, H., Hirabayashi, M., Ito, K., Ueda, M., Nabeshima, Y., Hino, O. (2002) Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system. Human Molecular Genetics, 11, 2997-3006. • Yeung, R. (2003) Multiple Roles of the Tuberous Sclerosis Complex Genes. Genes, Chromosomes & Cancer. 38. 368-375. • Ali, M., Girimaji, SC., Markandaya, M., Shukula, AK., Sacchidanand, S., Kumar, A. (2005) Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neural Scand. 111. 54-63. • Goncharova, E., Goncharov, D., Noonan, D., Krymskaya, V. (2004). TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. The Journal of Cell Biology. 167. 1171-1182. • Nellist, M., Sancak, O., Goedbloed, M., Rohe, C., van Netten, D., Mayer, K., Tucker-Williams, A., van den Ouweland, A., Halley, D. (2005). Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. European Journal of Human Genetics. 13. 59-68. • Lee, L., Sudentas, P., Donohue, B., Asrican, K., Worku, A., Walker,V., Sun, Y., Schmidt, K., Albert, M., El-Hashemite, N., Lader, A., Onda, H., Zhang, H., Kwiatkowski, D., Dabora, S. (2005). Efficacy of a rapamycin analog (CCI-779) and IFN- in tuberous sclerosis mouse models. Genes, Chromosomes & Cancer. 42(3). 213-227.

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