A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.
A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.
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DOI：
10.1002/acn3.320
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发表时间：
2016-07
影响因子：
5.3
通讯作者：
Strug LJ
中科院分区：
文献类型：
--
作者：
Panjwani N;Wilson MD;Addis L;Crosbie J;Wirrell E;Auvin S;Caraballo RH;Kinali M;McCormick D;Oren C;Taylor J;Trounce J;Clarke T;Akman CI;Kugler SL;Mandelbaum DE;McGoldrick P;Wolf SM;Arnold P;Schachar R;Pal DK;Strug LJ
Rolandic癫痫是一种常见的儿童遗传性局灶性癫痫，脑电图以中央颞区尖波为特征。在之前的全基因组分析中，我们已经报道了centrotemporal尖波与染色体11 p13的连锁，并且在两个独立的美国和加拿大病例对照样本中用44个SNP进行了精细定位，确定了ELP 4-PAX 6基因座。在这里，我们的目的是找到一个致病的变异，中央颞尖波使用更大的样本和更高分辨率的基因分型阵列。我们使用Illumina HumanCoreExome-12 v1.0 BeadChip在来自罗兰癫痫家族的186名个体和1000名欧洲血统的人群对照中精细定位了ELP 4-PAX 6基因座。使用主成分分析将对照组与种族病例相匹配。我们使用广义估计方程来评估关联，随后进行生物信息学调查和文献检索来评估功能意义。PAX 6 3′非翻译区SNP rs662702的T等位基因纯合性增加了CTS的风险：比值比= 12.29（95%CI：3.20-47.22），P = 2.6 × 10−4，在3.9%的病例中观察到，但在对照组中仅为0.3%。SNP rs662702的次要T等位基因破坏了microRNA-328的调控，已知这会导致体外PAX 6表达增加。这项研究首次提供了非编码基因组变异通过转录后调控机制导致人类常见癫痫病因学的证据。
Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome‐wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4‐PAX6 locus in two independent US and Canadian case–control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. We fine‐mapped the ELP4‐PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome‐12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. Homozygosity at the T allele of SNP rs662702 in the 3′ untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20–47.22), P = 2.6 × 10−4 and is seen in 3.9% of cases but only 0.3% of controls. The minor T allele of SNP rs662702 disrupts regulation by microRNA‐328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.