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Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon

机译:meis1中不安定腿部综合征相关的内含子常见变异改变了发育中的端脑中的增强子功能

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摘要

Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
机译:全基因组关联研究(GWAS)确定了躁郁症综合征(RLS)的MEIS1基因座,但因果单核苷酸多态性(SNPs)及其功能相关性仍然未知。该基因座包含大量的高度保守的非编码区(HCNR),可能充当顺式调控模块。我们分析了这些HCNRs在斑马鱼和小鼠中的等位基因依赖性增强子活性,发现铅SNP rs12469063的风险等位基因降低了鼠胚胎神经节突起(GE)Meis1表达域中的增强子活性。 CREB1与该增强子结合,而rs12469063在体外影响其结合。此外,MEIS1目标基因暗示在GE中神经元祖细胞的规格中发挥作用,杂合的Meis1缺陷型小鼠表现出过度活跃,类似于RLS表型。因此,对具有较小影响大小的常见SNP的体内和体外分析显示,前瞻性基底神经节中的等位基因依赖性功能代表了涉及RLS的第一个神经发育区域。

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