Get access

Gene Expression Analysis of Tuberous Sclerosis Complex Cortical Tubers Reveals Increased Expression of Adhesion and Inflammatory Factors

Authors

  • Karin Boer,

    1. Department of (Neuro)Pathology, Academic Medical Center,
    Search for more papers by this author
    • The first three authors contributed equally to the present work and are listed alphabetically.

  • Peter B. Crino,

    1. PENN Epilepsy Center, Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
    Search for more papers by this author
    • The first three authors contributed equally to the present work and are listed alphabetically.

  • Jan A. Gorter,

    1. Center for Neuroscience,
    2. Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands.
    Search for more papers by this author
    • The first three authors contributed equally to the present work and are listed alphabetically.

  • Mark Nellist,

    1. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
    Search for more papers by this author
  • Floor E. Jansen,

    1. Departments of Child Neurology, Pathology and Neurosurgery/Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands.
    Search for more papers by this author
  • Wim G.M. Spliet,

    1. Departments of Child Neurology, Pathology and Neurosurgery/Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands.
    Search for more papers by this author
  • Peter C. Van Rijen,

    1. Departments of Child Neurology, Pathology and Neurosurgery/Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands.
    Search for more papers by this author
  • Floyd R.A. Wittink,

    1. MicroArray Department, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
    Search for more papers by this author
  • Timo M. Breit,

    1. MicroArray Department, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
    Search for more papers by this author
  • Dirk Troost,

    1. Department of (Neuro)Pathology, Academic Medical Center,
    Search for more papers by this author
  • Wytse J. Wadman,

    1. Center for Neuroscience,
    Search for more papers by this author
  • Eleonora Aronica

    Corresponding author
    1. Department of (Neuro)Pathology, Academic Medical Center,
    2. Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands.
    Search for more papers by this author

Dr. E. Aronica, Dept. (Neuro)Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (E-mail: e.aronica@amc.uva.nl)

Abstract

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.

Ancillary