Identification of a region required for TSC1 stability by functional analysis of TSC1missense mutations found in individuals with tuberous sclerosis complex
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Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Recently it has been shown that missense mutations to the TSC1 gene can cause TSC. Methods: We have used in vitro biochemical assays to investigate the effects on TSC1 function of TSC1 missense variants submitted to the Leiden Open Variation Database. Results: We identified specific substitutions between amino acids 50 and 190 in the N-terminal region of TSC1 that result in reduced steady state levels of the protein and lead to increased mTOR signalling. Conclusion: Our results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1-TSC2 complex.
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The TSC1 core domain is considered essential for the stability of TSC1.
“The core domain is considered essential for the stability of TSC1 (Hoogeveen-Westerveld et al., 2010; Mozaffari et al., 2009);”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Mozaffari et al., 2009
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- Authors
- Mozaffari, M., Hoogeveen-Westerveld, M., Kwiatkowski, D., Sampson, J., Ekong, R., Povey, S., den Dunnen, J. T., van den Ouweland, A., Halley, D., & Nellist, M.
- Affiliations
- Erasmus MC (NL)
- Brigham and Women's Hospital (US)
- Cardiff University (GB)
- University College London (GB)
- Corresponding author
- Nellist, Mark
- Venue
- BMC Medical Genetics
- Published
- 2009-09-11
- Volume
- 10
- Issue
- 1
- Pages
- 88-88
- ISSN
- 1471-2350 (ISSN-L)
- PMC
- PMC2753308
- OpenAlex
- W2160066390
- Cited by
- 36
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 6 · 2013: 4 · 2012: 3
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Medical Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- U.S. Department of Defense
- Tuberous Sclerosis Alliance
- National Institutes of Health (NS31535)
- National Institute of Neurological Disorders and Stroke (NS-31535, R37NS031535, R01NS031535)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- tuberous sclerosis complex, TSC1, missense mutations, protein stability, N-terminal domain, TSC1/TSC2 complex, mTOR signaling, hamartoma, genotype-phenotype correlation
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Cell Line, Humans, Microscopy, Fluorescence, Protein Kinases, Tuberous Sclerosis, Signal Transduction, Amino Acid Substitution, Mutation, Missense, Tumor Suppressor Proteins, TOR Serine-Threonine Kinases
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