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.

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Journal European Journal of Human Genetics
Nellist, M, van den Heuvel, D, Schluep, D, Exalto, C, Goedbloed, M.A, Maat-Kievit, A.A, … Halley, D. (2009). Missense mutations to the TSC1 gene cause tuberous sclerosis complex. European Journal of Human Genetics, 17(3), 319–328. doi:10.1038/ejhg.2008.170