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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

BACKGROUND: 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 reg...

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Autores principales: Li, Tian, Kuang, Yaoyun, Li, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966731/
https://www.ncbi.nlm.nih.gov/pubmed/27473590
http://dx.doi.org/10.1186/s12863-016-0417-y
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author Li, Tian
Kuang, Yaoyun
Li, Bin
author_facet Li, Tian
Kuang, Yaoyun
Li, Bin
author_sort Li, Tian
collection PubMed
description BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-016-0417-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-49667312016-07-30 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 Li, Tian Kuang, Yaoyun Li, Bin BMC Genet Research Article BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-016-0417-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-07-29 /pmc/articles/PMC4966731/ /pubmed/27473590 http://dx.doi.org/10.1186/s12863-016-0417-y Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Li, Tian
Kuang, Yaoyun
Li, Bin
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort genetic variants in 3’ untranslated region of voltage-gated sodium channel alpha 1 subunit gene affect the mrna-microrna interactions and associate with epilepsy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966731/
https://www.ncbi.nlm.nih.gov/pubmed/27473590
http://dx.doi.org/10.1186/s12863-016-0417-y
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