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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

Tuberous Sclerosis TSC2

Morgan von Drehle

tuberous sclerosis
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
major features
Major Features
  • Neurological disorder
  • Tubers, fibromas, hamartomas
  • Discoloration of skin patches

http://www.emedicine.com/neuro/topic386.htm

minor features
Minor Features
  • Rectal polyps
  • Cysts
  • Ginigival fibromas
  • Skin lesions

http://www.emedicine.com/neuro/topic386.htm

slide5
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

tuberin
Tuberin
  • Protein product of TSC2
  • 200kD protein
  • 7 functional domains
  • Forms Tuberin Sclerosis Complex with TSC1

Goncharova et al.

mtor pathway
mTOR pathway

http://www.biocarta.com/pathfiles/h_mTORPathway.asp

mutations in tsc2
Mutations in TSC2
  • Splice site mutations
  • Deletions
  • Insertions
  • Missense mutations
  • Nonsense mutations

Nellist et al.

single amino acid change
Single Amino Acid Change

COS Cells

Nellist et al.

treatments
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.

references
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.