1. ¹Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
2. ²Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
3. ³Department of Child Neurology, Rudolf Magnus Institute for Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands
4. ⁴Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
5. ⁵Department of Clinical Pediatrics, University of Siena, Siena, Italy
6. ⁶Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
7. ⁷Clinical Genetics Unit, Department of Pediatrics, Turku University Central Hospital, Turku, Finland
8. ⁸Centre of Medical Genetics, University of Antwerp, Antwerp, Belgium

Correspondence: Dr M Nellist, Department of Clinical Genetics, Erasmus Medical Centre, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Tel: +31 10 7043357; Fax: +31 10 7044736; E-mail: m.nellist@erasmusmc.nl

Received 2 May 2008; Revised 16 July 2008; Accepted 27 August 2008; Published online 1 October 2008.

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, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1–TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC.