Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex

Marianne Hoogeveen - Westerveld, R Ekong, S Povey, I Karbassi, SD Batish, JT Dunnen, Agnies van Eeghen, E Thiele, K Mayer, K Dies, L Wen, C Thompson, SP Sparagana, P Davies, C Aalfs, Ans van den Ouweland, Dicky Halley, Mark Nellist

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Scopus)


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 50224) 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. Hum Mutat 33:476479, 2012. (C) 2011 Wiley Periodicals, Inc.
Original languageUndefined/Unknown
Pages (from-to)476-479
Number of pages4
JournalHuman Mutation
Issue number3
Publication statusPublished - 2012

Cite this