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

• Main Authors: den Dunnen Johan T (Author), Povey Sue (Author), Ekong Rosemary (Author), Sampson Julian (Author), Kwiatkowski David (Author), Hoogeveen-Westerveld Marianne (Author), Mozaffari Melika (Author), van den Ouweland Ans (Author), Halley Dicky (Author), Nellist Mark (Author)
• Format: Book
• Published: BMC, 2009-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<p>Abstract</p> <p>Background</p> <p>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 <it>TSC1 </it>gene on chromosome 9q34, or the <it>TSC2 </it>gene on chromosome 16p13.3. The <it>TSC1 </it>and <it>TSC2 </it>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 <it>TSC1 </it>gene can cause TSC.</p> <p>Methods</p> <p>We have used <it>in vitro </it>biochemical assays to investigate the effects on TSC1 function of <it>TSC1 </it>missense variants submitted to the Leiden Open Variation Database.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>

Item Description

10.1186/1471-2350-10-88
1471-2350