Department of Human Genetics, McGill University, Montréal, QC, Canada.
Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Eur J Hum Genet. 2020 Nov;28(11):1520-1528. doi: 10.1038/s41431-020-0670-4. Epub 2020 Jun 22.
Restless legs syndrome (RLS) is a common sleep-related sensory-motor disorder. It is characterized by uncomfortable sensations in the legs during the evening or at night. The symptoms can be partially relieved by movement, so typically affected individual needs to walk during rest time; this interferes with sleep. GWAS have identified 19 RLS-associated loci. Among the first to be reported and most significant and robustly replicated reports are variants in the SKOR1 noncoding regions. SKOR1 is highly expressed in the CNS of humans and mice. Skor1 acts as a corepressor of Lbx1 transcription factor in mice and these two genes act together to regulate the cell fate of interneurons in the dorsal horn of the spinal cord. Based on this data we investigated the regulatory role of SKOR1 using a global RNA-sequencing approach in human cell lines where SKOR1 was either overexpressed or silenced. For this work we generated and validated a new poly-clonal anti-SKOR1. Pathway and gene set enrichment analyses of the differentially expressed genes showed, among others, enrichment of genes involved in neurodevelopment and iron metabolism, two RLS relevant pathways that were previously found to be enriched in the latest RLS GWAS meta-analysis. Analysis of our different datasets further supports and highlights the regulatory role of SKOR1, which when dysregulated might represent a key pathogenic element of RLS. A better understanding of SKOR1 and its activity could open new avenues of investigation for the development of a much-needed therapy.
不宁腿综合征（RLS）是一种常见的与睡眠相关的感觉运动障碍。其特征是在傍晚或夜间腿部出现不适感觉。症状可通过运动部分缓解，因此受影响的个体通常需要在休息时间走动；这会干扰睡眠。全基因组关联研究（GWAS）已经确定了 19 个与 RLS 相关的基因座。在最先报道的和最显著和最有力复制的报告中，有 SKOR1 非编码区域的变异。SKOR1 在人类和小鼠的中枢神经系统中高度表达。在小鼠中，Skor1 作为 Lbx1 转录因子的核心抑制物起作用，这两个基因共同作用调节脊髓背角中间神经元的细胞命运。基于这些数据，我们使用人类细胞系中的全 RNA 测序方法研究了 SKOR1 的调节作用，在这些细胞系中，SKOR1 被过表达或沉默。为此，我们生成并验证了一种新的多克隆抗 SKOR1。差异表达基因的通路和基因集富集分析显示，除其他外，富集了与神经发育和铁代谢相关的基因，这两个 RLS 相关通路在前一次 RLS GWAS 荟萃分析中被发现富集。对我们不同数据集的分析进一步支持和强调了 SKOR1 的调节作用，当 SKOR1 失调时，可能代表 RLS 的一个关键致病因素。对 SKOR1 及其活性的更好理解可能为开发急需的治疗方法开辟新的研究途径。
