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Tuberous Sclerosis

Tuberous Sclerosis. TSC2/ Tuberin. Alison Chappell. Objectives. Characteristics of Disease TSC 2 gene Hypothetical biochemical function of TSC 2/ Tuberin Mutations and their effects. Tuberous Sclerosis.

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Tuberous Sclerosis

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  1. Tuberous Sclerosis TSC2/ Tuberin Alison Chappell

  2. Objectives • Characteristics of Disease • TSC 2 gene • Hypothetical biochemical function of TSC 2/ Tuberin • Mutations and their effects

  3. Tuberous Sclerosis • At least two children are born each day with TS. Affects 50,000 Americans and 2 million people worldwide. • Affects multiple organs and is characterized by hamartomas (benign tumor cells) • Although, the tumors rarely into malignancy they can cause various problems and difficulties.

  4. Major Features of TSC • Major Organs: Skin, Heart, Brain, and Kidney • Skin: facial angiofibromas (most distinctive feature, displayed in 70% of all TSC patients), hypomelanotic macules • Heart: rhabdomypomas and arrhythmias

  5. Major Features of TSC • Brain: cortical tubers, subependymal noduals, giant cell astrocytomas (15%), seizures (60-90%), mental retardation/ developmental delay • Kidney: angiomyolipomas, cysts

  6. Inheritance / Penetrance • 33 % of TSC patients inherit a mutation from their parents. • The other 66% of TSC patients develop disease due to sporadic mutations from the parent passed on to the child. • 100 % penetrance • Autosomal Dominate Disorder yet recessive on the cellular level

  7. TSC 2 gene • TSC 2 is located at 16p13 and encodes the amino acid protein, Tuberin. • Functional Regions: • C- Terminus: the GTP-ase activating protein homology (GAP) for Rap 5 and Rap 1 • Coiled- Coil domain- interaction with TSC 1/ Harmartin Goncharova et al. 2002

  8. Hypothetical Biochemistry of TSC • TSC is possibly involved cell cycle regulation, vesicular trafficking, and transcriptional activation by steroid hormone • Genetic approach- clone of TSC 2 • Tuberin is highly conserved between organisms- Drosphila • Increased growth (increase of mass per unit time) and proliferation (an increase in cell number) Increased size of wing and eye with TSC 2 mutation. Ito.ed al 1999

  9. Model of Tuberin- Hamartin complex and mTOR pathway Tee et.al 2002

  10. mTOR pathway • Insulin major regulator of cellular growth • Tuberin/ Harmartin complex act as a tumor suppressor on mTOR • mTOR (active) allows for the phosphorylation of S6 by S6K and the inactivation of the 4E-BP1 (4E binding protein- eukaryotic initiation factor) • 5’TOP mRNA (5’ terminal oligopyrimidine tract)- encode ribosomal proteins and several other components of translational machinery leading to increased cell growth

  11. McManus, et al. 2002

  12. mTOR pathway, continued. • PI(3)K (phosphoinositide-3-kinase) is recruited to the plasma membrane in response to stimulation with growth factors as insulin. • PI(3)K generates a lipid second messenger phosphatidylinositol-3,4,5-trisphosphate induces PKB (Akt) and S6K activation.

  13. Tuberin and Rap 1 • Tuberin’s GAP activity forrap1 and rap5. • Rap 1 and Rap 5 are members of the Rassuperfamily of GTPases serveroles in mitogenesis,neuronal differentiation, and earlyendosome fusion. • Little research since 1997

  14. TSC mutations • Mutation in TSC 1 or TSC 2 result in the same clinical abnormalities. • Mutation in TSC 1 or 2 in Drosophila revealed cells spend less time in G1 and inappropriately entered the cell cycle when they should have been quiescent. • The result of these mutations were larger cells with normal ploidy. (Tapon et al 2002)

  15. TSC 2 mutations • TSC2 mutations include large deletions, insertions and rearrangements (>1kb) and a significant number of missense mutations • Many mutations localized in the GAP region and a few in the binding region of Tuberin to Hamartin

  16. TSC 2 mutations • In HEK293 cells, derived from humanembryonic kidney cells, Soueke studied the effects of TSC 1 and TSC 2 on cells. (Soucek, et.al 1998) • The data suggest that tuberin (TSC 2), not hamartin (TSC1),is responsible for G1 regulation by the hamartin-tuberin complex. • Increased Intellectual disability with mutations in TSC 2 (Jones et.al 1999)

  17. Summary • Tuberous Sclerosis is an autosomal dominate disorder characterized by harmatomas (benign tumors). • TSC 2 produces the protein, Tuberin, has a GTP- ase (GAP) activating region and a coiled- coil domain which facilitates binding to Hamartin (TSC1). • The biochemical function of TSC is unclear yet best evidence is TSC involvement in the mTOR/ insulin pathway.

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