title: Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N-terminal domain of TSC1 (amino acids 50-224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1-TSC2-dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N-terminal region of TSC1 is essential for TSC1 function.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ekong
authors.forename: Sue
authors.initials: S
authors.lastname: Povey
authors.forename: Izabela
authors.initials: I
authors.lastname: Karbassi
authors.forename: Sat Dev
authors.initials: SD
authors.lastname: Batish
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Agnies
authors.initials: A
authors.lastname: van Eeghen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thiele
authors.forename: Karin
authors.initials: K
authors.lastname: Mayer
authors.forename: Kira
authors.initials: K
authors.lastname: Dies
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: Catherine
authors.initials: C
authors.lastname: Thompson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Sparagana
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Cora
authors.initials: C
authors.lastname: Aalfs
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Dicky
authors.initials: D
authors.lastname: Halley
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
mesh_terms: D000818:Animals; D006801:Humans; D015151:Immunoblotting; D020125:Mutation, Missense / Q000235:genetics*; 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