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Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex

Mozaffari, Melika, Hoogeveen-Westerveld, Marianne, Kwiatkowski, David, Sampson, Julian Roy, Ekong, Rosemary, Povey, Sue, den Dunnen, Johan T., van den Ouweland, Ans, Halley, Dicky and Nellist, Mark 2009. Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Medical Genetics 10 , pp. 1-12. 10.1186/1471-2350-10-88

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/1471-2350/ (accessed 25/02/2014)
Publisher: BioMed Central
ISSN: 1471-2350
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:53
URI: http://orca-mwe.cf.ac.uk/id/eprint/28495

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