title: The genetic variants in 3' untranslated region of voltage-gated sodium channel alpha 1 subunit gene affect the mRNA-microRNA interactions and associate with epilepsy.
abstract: mRNA expression in a cell or subcellular organelle is precisely regulated for the purpose of gene function regulation. The 3' untranslated region (3'UTR) of mRNA is the binding target of microRNA and RNA binding proteins. Their interactions regulate mRNA level in specific subcellular regions and determine the intensity of gene repression. The mutations in the coding region of voltage-gated sodium channel alpha 1 subunit gene, SCN1A, were identified in epileptic patients and confirmed as causative factors of epilepsy. We investigated if there were genetic variants in 3'UTR of SCN1A, affecting the microRNA-mRNA 3'UTR interaction and SCN1A gene repression, potentially associated with epilepsy.
  
  
  
  In this case-control study, we identified twelve variants, NM_001202435.1:n.6277A > G, n.6568_6571del, n.6761C > T, n.6874A > T, n.6907 T > C, n.6978A > G, n.7065_7066insG, n.7282 T > C, n.7338_7344del, n.7385 T > A, n.7996C > T, and n.8212C > T in 3'UTR of SCN1A gene. We found that the variant of n.6978A > G in all our samples was completely mutated (G/G). In male group, T allele in n.7282 T > C was associated with epilepsy, while C allele was significantly less frequent in epileptic patients than in normal males (OR 0.424). Consequently, the haplotype "CTTACATGACGA" / "CTCTA" was significantly less frequent in male epileptic patients (0.173) than in normal males (0.305). The frequency of haplotype block found in females, "TTTAACA", "TTCAACA", and "CTTAACA" was 0.499, 0.254 and 0.234 respectively. Within STarMir model analysis, the "CTCTA" haplotype showed significantly higher site accessibility to microRNA targeting and higher downstream sequence accessibility for nonconserved binding than that of other haplotypes. Overall, the male genotypes have the higher accessibility of the downstream 30nt block of nonconserved site than the female genotypes.
  
  
  
  NM_001202435.1:n.7282 T > C is the genetic variant associated with epilepsy in males, and the related haplotype "CTTACATGACGA" / "CTCTA" in the region of chr2: 165991297-165989081, which has high site accessibility for microRNA binding, is the genetic protective factor against epilepsy in males. In female subset, the frequencies of haplotype block "TTTAACA", "TTCAACA", and "CTTAACA" were 0.499,0.254 and 0.234 respectively. Alleles and haplotypes distribution did not differ in female cases in comparison to female controls.
authors.affiliation: Center for Cognitive Neurology, New York University Langone Medical Center, New York, NY, 10016, USA. tl1913@nyu.edu.|Silver School of Social Work, New York University, New York, NY, 10003, USA. tl1913@nyu.edu.
authors.forename: Tian
authors.identifier: 0000-0003-0956-928X
authors.initials: T
authors.lastname: Li
authors.affiliation: Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, The Ministry of Education, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, China.
authors.forename: Yaoyun
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, The Ministry of Education, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Epilepsy; Haplotype; SNP; Untranslated region; microRNA