Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.
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). Here, we investigate the effects of 78 TSC2 variants identified in individuals suspected of TSC, on the function of the TSC1-TSC2 complex. According to our functional assessment, 40 variants disrupted the TSC1-TSC2-dependent inhibition of TORC1. We classified 34 of these as pathogenic, three as probably pathogenic and three as possibly pathogenic. In one case, a likely effect on splicing as well as an effect on function was noted. In 15 cases, our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our data support the notion that different, nonterminating TSC2 mutations can have distinct effects on TSC1-TSC2 function, and therefore, on TSC pathology.
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
Marianne
M
Hoogeveen-Westerveld
Rosemary
R
Ekong
Sue
S
Povey
Karin
K
Mayer
Nathalie
N
Lannoy
Frances
F
Elmslie
Martina
M
Bebin
Kira
K
Dies
Catherine
C
Thompson
Steven P
SP
Sparagana
Peter
P
Davies
Agnies M
AM
van Eeghen
Elizabeth A
EA
Thiele
Ans
A
van den Ouweland
Dicky
D
Halley
Mark
M
Nellist
D019943:Amino Acid Substitution; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases