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An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters
Author(s) -
Mirza Nasir,
Vasieva Olga,
Appleton Richard,
Burn Sasha,
Carr Daniel,
Crooks Daniel,
du Plessis Daniel,
Duncan Roderick,
Farah Jibril Osman,
Josan Vivek,
Miyajima Fabio,
Mohanraj Rajiv,
Shukralla Arif,
Sills Graeme J.,
Marson Anthony G.,
Pirmohamed Munir
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13473
Subject(s) - in silico , epilepsy , ex vivo , computational biology , epileptogenesis , biology , bioinformatics , neuroscience , gene , medicine , in vivo , genetics
Summary Objective 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 SLC s. SLC s have never been systematically studied in epilepsy. Methods Using our in silico system, we predicted the SLC s likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLC s 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 SLC s to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls. Results There was a highly significant (p < 9.99 × 10 −7 ) overlap between the genes identified by our in silico and ex vivo strategies. The SLC s identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability. Significance The identified SLC s 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.