Sarayloo Faezeh, Dion Patrick A, Rouleau Guy A
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Front Neurol. 2019 Aug 28;10:935. doi: 10.3389/fneur.2019.00935. eCollection 2019.
Restless legs syndrome (RLS) is a common sleep-related disorder for which the underlying biological pathways and genetic determinants are not well understood. The genetic factors so far identified explain less than 10% of the disease heritability. The first successful genome-wide association study (GWAS) of RLS was reported in 2007. This study identified multiple RLS associated risk variants including some within the non-coding regions of . The GWAS signals are some of the strongest genetic associations reported for any common disease. MEIS1 belongs to the homeobox containing transcriptional regulatory network (HOX). Work in showed a link between the ortholog and iron homeostasis, which is in line with the fact that central nervous system (CNS) iron insufficiency is thought to be a cause of RLS. Zebrafish and mice have been used to study the gene identifying an RLS-associated-SNP dependent enhancer activity from the highly conserved non-coding regions (HCNR) of . Furthermore, this gene shows a lower expression of mRNA and protein in blood and thalamus of individuals with the RLS risk haplotype. Simulating this reduced expression in mouse models resulted in circadian hyperactivity, a phenotype compatible with RLS. While shows a strong association with RLS, the protein's function that is directly linked to an RLS biological pathway remains to be discovered. The links to iron and the enhancer activity of the HCNRs of suggest promising links to RLS pathways, however more in-depth studies on this gene's function are required. One important aspect of 's role in RLS is the fact that it encodes a homeobox containing transcription factor, which is essential during development. Future studies with more focus on the transcriptional regulatory role of MEIS1 may open novel venues for RLS research.
不宁腿综合征（RLS）是一种常见的与睡眠相关的疾病，其潜在的生物学途径和遗传决定因素尚未完全明确。迄今为止确定的遗传因素仅解释了不到10%的疾病遗传性。2007年报道了第一项成功的不宁腿综合征全基因组关联研究（GWAS）。这项研究确定了多个与不宁腿综合征相关的风险变异，包括一些位于……非编码区域内的变异。这些GWAS信号是任何常见疾病所报道的最强的遗传关联之一。MEIS1属于包含转录调控网络（HOX）的同源盒基因。……的研究表明该同源基因与铁稳态之间存在联系，这与中枢神经系统（CNS）铁缺乏被认为是不宁腿综合征病因这一事实相符。斑马鱼和小鼠已被用于研究该基因，从……的高度保守非编码区域（HCNR）中鉴定出一种与不宁腿综合征相关的单核苷酸多态性（SNP）依赖性增强子活性。此外，该基因在具有不宁腿综合征风险单倍型的个体的血液和丘脑中显示出较低的mRNA和蛋白质表达。在小鼠模型中模拟这种降低的……表达导致昼夜活动亢进，这是一种与不宁腿综合征相符的表型。虽然……与不宁腿综合征有很强的关联，但与不宁腿综合征生物学途径直接相关的蛋白质功能仍有待发现。与铁的联系以及……的HCNR的增强子活性表明与不宁腿综合征途径有潜在的联系，然而需要对该基因的功能进行更深入的研究。……在不宁腿综合征中的作用的一个重要方面是它编码一种包含转录因子的同源盒基因，这在发育过程中是必不可少的。未来更多关注MEIS1转录调控作用的研究可能会为不宁腿综合征研究开辟新的途径。
