title: An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters.
abstract: Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource-intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy.
  
  
  
  Using our in silico system, we predicted the SLCs likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLCs dysregulated in epileptic foci, and determining the overlap between our in silico and ex vivo results. For the ex vivo analysis, we used a custom oligonucleotide microarray containing exon probes for all known SLCs to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls.
  
  
  
  There was a highly significant (p < 9.99 × 10(-7) ) overlap between the genes identified by our in silico and ex vivo strategies. The SLCs identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability.
  
  
  
  The identified SLCs are most likely to mediate pharmacoresistance in epilepsy by enhancing the intrinsic severity of epilepsy, but further functional work will be needed to fully evaluate their role. Our successful in silico strategy can be adapted in order to prioritize genes relevant to epilepsy from other gene families.
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Nasir
authors.initials: N
authors.lastname: Mirza
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Vasieva
authors.affiliation: The Roald Dahl EEG Unit, Paediatric Neurosciences Foundation, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Appleton
authors.affiliation: Department of Neurosurgery, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Sasha
authors.initials: S
authors.lastname: Burn
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carr
authors.affiliation: Department of Neuropathology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Crooks
authors.affiliation: Department of Cellular Pathology, Salford Royal NHS Foundation Trust, Salford, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: du Plessis
authors.affiliation: Department of Neurology, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Roderick
authors.initials: R
authors.lastname: Duncan
authors.affiliation: Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Jibril Osman
authors.initials: JO
authors.lastname: Farah
authors.affiliation: Department of Neurosurgery, Salford Royal NHS Foundation Trust, Salford, United Kingdom.
authors.forename: Vivek
authors.initials: V
authors.lastname: Josan
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Fabio
authors.initials: F
authors.lastname: Miyajima
authors.affiliation: Department of Neurology, Salford Royal NHS Foundation Trust, Salford, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Mohanraj
authors.affiliation: Department of Neurology, Salford Royal NHS Foundation Trust, Salford, United Kingdom.
authors.forename: Arif
authors.initials: A
authors.lastname: Shukralla
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Sills
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Marson
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D019295:Computational Biology; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins
keywords: Computational gene prioritization; Convergent functional genomics; Epilepsy; Hippocampal sclerosis; Microarray; Pharmacoresistance; Solute carrier transporters