Missense mutations to the TSC1 gene cause tuberous sclerosis complex
Mark Nellist1, Diana van den Heuvel, Diane Schluep
1Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. m.nellist@erasmusmc.nl
European Journal of Human Genetics : EJHG
|October 3, 2008
Summary
Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes. Specific TSC1 mutations disrupt the TSC1-TSC2 complex, activating mTOR signaling and causing TSC symptoms.
Area of Science:
- Genetics
- Molecular Biology
- Cell Signaling
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant disorder.
- It results from mutations in TSC1 or TSC2 genes, affecting hamartoma development.
- The TSC1 and TSC2 proteins form a complex inhibiting mammalian target of rapamycin (mTOR) signaling.
Purpose of the Study:
- Investigate the impact of TSC1 missense mutations on TSC1-TSC2 complex formation.
- Analyze the effects of these mutations on mTOR signaling pathways.
- Correlate molecular changes with TSC symptoms.
Main Methods:
- Analysis of putative TSC1 missense mutations.
- Assessment of TSC1-TSC2 protein complex stability.
- Monitoring of mTOR signaling pathway activity.
Main Results:
- Specific N-terminal TSC1 amino-acid substitutions reduce TSC1 protein levels.
- This reduction leads to impaired TSC1-TSC2 complex formation.
- Consequent activation of mTOR signaling pathways is observed.
Conclusions:
- Missense mutations in TSC1 can destabilize the TSC1-TSC2 complex.
- Disruption of this complex activates mTOR signaling, contributing to TSC pathogenesis.
- Understanding these mechanisms may inform therapeutic strategies for TSC.
Related Concept Videos
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:20The Retinoblastoma Gene
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:39Mutations
Overview