Missense mutations to the TSC1 gene cause tuberous sclerosis complex.
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.
Nellist
Mark
M
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. m.nellist@erasmusmc.nl
van den Heuvel
Diana
D
Schluep
Diane
D
Exalto
Carla
C
Goedbloed
Miriam
M
Maat-Kievit
Anneke
A
van Essen
Ton
T
van Spaendonck-Zwarts
Karin
K
Jansen
Floor
F
Helderman
Paula
P
Bartalini
Gabriella
G
Vierimaa
Outi
O
Penttinen
Maila
M
van den Ende
Jenneke
J
van den Ouweland
Ans
A
Halley
Dicky
D
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
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