TY - JOUR
T1 - Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex
AU - Hoogeveen-Westerveld, Marianne
AU - Ekong, Rosemary
AU - Povey, Sue
AU - Karbassi, Izabela
AU - Batish, Sat Dev
AU - den Dunnen, Johan T.
AU - van Eeghen, Agnies
AU - Thiele, Elizabeth
AU - Mayer, Karin
AU - Dies, Kira
AU - Wen, Li
AU - Thompson, Catherine
AU - Sparagana, Steven P.
AU - Davies, Peter
AU - Aalfs, Cora
AU - van den Ouweland, Ans
AU - Halley, Dicky
AU - Nellist, Mark
PY - 2012
Y1 - 2012
N2 - 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. © 2011 Wiley-Liss, Inc.
AB - 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. © 2011 Wiley-Liss, Inc.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84857064426&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/22161988
U2 - https://doi.org/10.1002/humu.22007
DO - https://doi.org/10.1002/humu.22007
M3 - Article
C2 - 22161988
SN - 1059-7794
VL - 33
SP - 476
EP - 479
JO - Human mutation
JF - Human mutation
IS - 3
ER -