Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors.
Cortical tubers in patients with tuberous sclerosis complex are associated with disabling neurological manifestations, including intractable epilepsy. While these malformations are believed to result from the effects of TSC1 or TSC2 gene mutations, the molecular mechanisms leading to tuber formation, as well as the onset of seizures, remain largely unknown. We used the Affymetrix Gene Chip platform to provide the first genome-wide investigation of gene expression in surgically resected tubers, compared with histological normal perituberal tissue from the same patients or autopsy control tissue. We identified 2501 differentially expressed genes in cortical tubers compared with autopsy controls. Expression of genes associated with cell adhesion, for example, VCAM1, integrins and CD44, or with the inflammatory response, including complement factors, serpinA3, CCL2 and several cytokines, was increased in cortical tubers, whereas genes related to synaptic transmission, for example, the glial glutamate transporter GLT-1, and voltage-gated channel activity, exhibited lower expression. Gene expression in perituberal cortex was distinct from autopsy control cortex suggesting that even in the absence of tissue pathology the transcriptome is altered in TSC. Changes in gene expression yield insights into new candidate genes that may contribute to tuber formation or seizure onset, representing new targets for potential therapeutic development.
Boer
Karin
K
Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Crino
Peter B
PB
Gorter
Jan A
JA
Nellist
Mark
M
Jansen
Floor E
FE
Spliet
Wim G M
WG
van Rijen
Peter C
PC
Wittink
Floyd R A
FR
Breit
Timo M
TM
Troost
Dirk
D
Wadman
Wytse J
WJ
Aronica
Eleonora
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007249:Inflammation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers