Introduction

The relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy.We identified a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy and for common variants associated with polygenic epilepsy. The genes in the M30 network are expressed widely in the human brain under tight developmental control and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within the M30 network were preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent downregulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the downregulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons.Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.

Publications

  1. Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery.
    Cite this
    Delahaye-Duriez A, Srivastava P, Shkura K, Langley SR, Laaniste L, Moreno-Moral A, Danis B, Mazzuferi M, Foerch P, Gazina EV, Richards K, Petrou S, Kaminski RM, Petretto E, Johnson MR, 2016-12-01 - Genome biology

Credits

  1. Andree Delahaye-Duriez
    Developer

    PROTECT, INSERM

  2. Prashant Srivastava
    Developer

    Division of Brain Sciences, Imperial College Faculty of Medicine

  3. Kirill Shkura
    Developer

    Division of Brain Sciences, Imperial College Faculty of Medicine

  4. Sarah R Langley
    Developer

    Duke-NUS Medical School, 8 College Road

  5. Liisi Laaniste
    Developer

    Division of Brain Sciences, Imperial College Faculty of Medicine

  6. Aida Moreno-Moral
    Developer

    Duke-NUS Medical School, 8 College Road

  7. Bénédicte Danis
    Developer

    Neuroscience TA, UCB Pharma, Belgium

  8. Manuela Mazzuferi
    Developer

    Neuroscience TA, UCB Pharma, Belgium

  9. Patrik Foerch
    Developer

    Neuroscience TA, UCB Pharma, Belgium

  10. Elena V Gazina
    Developer

    The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia

  11. Kay Richards
    Developer

    The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia

  12. Steven Petrou
    Developer

    The Australian Research Council Centre of Excellence for Integrative Brain Function, Parkville, Australia

  13. Rafal M Kaminski
    Developer

    Neuroscience TA, UCB Pharma, Belgium

  14. Enrico Petretto
    Developer

    Duke-NUS Medical School, 8 College Road

  15. Michael R Johnson
    Investigator

    Division of Brain Sciences, Imperial College Faculty of Medicine

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Summary
AccessionBT001963
Tool TypeApplication
Category
PlatformsLinux/Unix
TechnologiesR
User InterfaceTerminal Command Line
Download Count0
Submitted ByMichael R Johnson