McGill University, Department of Human Genetics, Montréal, QC, Canada.
McGill University, Montreal Neurological Institute, Montréal, QC, Canada.
PLoS One. 2019 Nov 14;14(11):e0225186. doi: 10.1371/journal.pone.0225186. eCollection 2019.
Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's diseases, this is a first report to propose that they have a role in RLS.
不宁腿综合征是一种常见的复杂疾病，具有不同的遗传和环境风险因素。在这里，我们使用人类细胞系进行了 RNA-Seq 研究，观察了与 RLS 关联最显著的基因 MEIS1 如何作为许多其他基因表达的调节剂。其表达水平受影响的一些基因与先前报道与 RLS 相关的途径有关。我们发现，在 MEIS1 表达增加或被阻止的细胞中，矿物质吸收是主要失调的途径。受矿物质吸收途径基因 HMOX1 和 VDR 影响的基因分别参与铁代谢和对维生素 D 的反应。这显示出与已知 RLS 途径的强烈功能联系。我们观察到 RLS 患者死后脑组织中也存在相同的矿物质吸收途径富集，这些患者的 MEIS1 表达降低。从人类细胞和组织生成的 RNA-Seq 数据集观察到编码金属硫蛋白 (MTs) 的基因表达失调。MTs 与 RLS 高度相关，因为它们结合细胞内金属，防止氧化应激，并与铁蛋白相互作用，铁蛋白可调节中枢神经系统中的铁水平。总体而言，我们的研究表明，在一部分 RLS 患者中，MEIS1 的作用似乎与其下游调节基因有关，这些基因更直接参与与 RLS 相关的途径。虽然 MTs 已被牵连到神经退行性疾病（如帕金森病）的发病机制中，但这是首次提出它们在 RLS 中起作用的报告。
