title: Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression.
abstract: OBJECTIVE
  Many antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels. However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes. We investigated the association of AED responsiveness with genetic polymorphisms and correlated any association with mRNA expression of the neuronal sodium channels.
  
  
  METHODS
  We performed genotyping of tagging and candidate single nucleotide polymorphisms (SNPs) of SCN1A, 2A, and 3A in 471 Chinese epilepsy patients (272 drug responsive and 199 drug resistant). A total of 27 SNPs were selected based on the HapMap database. Genotype distributions in drug-responsive and drug-resistant patients were compared. SCN2A mRNA was quantified by real-time PCR in 24 brain and 57 blood samples. Its level was compared between patients with different genotypes of an SCN2A SNP found to be associated with drug responsiveness.
  
  
  RESULTS
  SCN2A IVS7-32A>G (rs2304016) A alleles were associated with drug resistance (odds ratio = 2.1, 95% confidence interval: 1.2-3.7, P=0.007). Haplotypes containing the IVS7-32A>G allele A were also associated with drug resistance. IVS7-32A>G is located within the putative splicing branch site for splicing exons 7 and 9. PCR of reverse-transcribed RNA from blood or brain of patients with different IVS7-32A>G genotypes using primers in exons 7 and 9 showed no skipping of exon 8, and real-time PCR showed no difference in SCN2A mRNA levels among genotypes.
  
  
  CONCLUSIONS
  Results of this study suggest an association between SCN2A IVS7-32A>G and AED responsiveness, without evidence of an effect on splicing or mRNA expression.
authors.affiliation: Division of Neurology, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China. patrickkwan@cuhk.edu.hk
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
authors.forename: David E
authors.initials: DE
authors.lastname: Kang
authors.forename: Virginia
authors.initials: V
authors.lastname: Wong
authors.forename: Ping Wing
authors.initials: PW
authors.lastname: Ng
authors.forename: Colin H T
authors.initials: CH
authors.lastname: Lui
authors.forename: Ngai Chuen
authors.initials: NC
authors.lastname: Sin
authors.forename: Ka S
authors.initials: KS
authors.lastname: Wong
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D015331:Cohort Studies; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008969:Molecular Sequence Data; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C424715:SCN3A protein, human; D015222:Sodium Channels