title: Missense mutations to the TSC1 gene cause tuberous sclerosis complex.
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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. m.nellist@erasmusmc.nl
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.forename: Diana
authors.initials: D
authors.lastname: van den Heuvel
authors.forename: Diane
authors.initials: D
authors.lastname: Schluep
authors.forename: Carla
authors.initials: C
authors.lastname: Exalto
authors.forename: Miriam
authors.initials: M
authors.lastname: Goedbloed
authors.forename: Anneke
authors.initials: A
authors.lastname: Maat-Kievit
authors.forename: Ton
authors.initials: T
authors.lastname: van Essen
authors.forename: Karin
authors.initials: K
authors.lastname: van Spaendonck-Zwarts
authors.forename: Floor
authors.initials: F
authors.lastname: Jansen
authors.forename: Paula
authors.initials: P
authors.lastname: Helderman
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bartalini
authors.forename: Outi
authors.initials: O
authors.lastname: Vierimaa
authors.forename: Maila
authors.initials: M
authors.lastname: Penttinen
authors.forename: Jenneke
authors.initials: J
authors.lastname: van den Ende
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Dicky
authors.initials: D
authors.lastname: Halley
mesh_terms: D019943:Amino Acid Substitution; D006801:Humans; D020125:Mutation, Missense; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases