Tuberous Sclerosis
TSC2/ Tuberin
Alison Chappell
Objectives
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Characteristics of Disease
TSC 2 gene
Hypothetical biochemical function of TSC 2/
Tuberin
Mutations and their effects
Tuberous Sclerosis
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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.
Major Features of TSC
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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
Major Features of TSC
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Brain: cortical tubers,
subependymal noduals,
giant cell astrocytomas
(15%), seizures (6090%), mental
retardation/
developmental delay
Kidney:
angiomyolipomas, cysts
Inheritance / Penetrance
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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
TSC 2 gene
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TSC 2 is located at 16p13 and encodes the amino acid protein,
Tuberin.
Functional Regions:
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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
Hypothetical Biochemistry of TSC
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TSC is possibly involved cell cycle regulation, vesicular trafficking,
and transcriptional activation by steroid hormone
Genetic approach- clone of TSC 2
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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
Model of Tuberin- Hamartin complex and mTOR pathway Tee et.al 2002
mTOR pathway
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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
McManus, et al.
2002
mTOR pathway, continued.
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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.
Tuberin and Rap 1
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Tuberin’s GAP activity for
rap1 and rap5.
Rap 1 and Rap 5 are
members of the Ras
superfamily of GTPases
serve roles in mitogenesis,
neuronal differentiation, and
early endosome fusion.
Little research since 1997
TSC mutations
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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)
TSC 2 mutations
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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
TSC 2 mutations
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In HEK293 cells, derived from human
embryonic 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)
Summary
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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.