Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs because of abnormal sensations. This usually develops when falling asleep or during the night. RLS can lead to severe sleep disturbances and impaired quality of life of those who are affected. This disorder has a strong genetic component and it is common with a prevalence ~5–10% across western populations.

A RLS genome wide association study conducted by Winkelmann et al. previously identified highly significant intronic variants in the homeobox gene MEIS1 and in the overlapping region between the genes MAP2K5 and SKOR1. Our group subsequently reported the MEIS1 intronic risk haplotype to reduce the expression of the gene at its mRNA and protein levels.

Given the GWAS results and our expression studies, we examined the mRNA expression of SKOR1 in cells and tissues of individuals with and without the MEIS1 risk genotype associated with the disease. We used quantitative RT-PCR and showed a decrease in SKOR1 mRNA expression in patients with risk allele, suggesting an interaction between MEIS1 and SKOR1. To further investigate the regulation of SKOR1 by MEIS1 we used a luciferase reporter assay using promoter regions of SKOR1.

Our data shows a strong association between these two genes, as MEIS1 appears to activate the expression of SKOR1 by binding its promoter at two specific sites.

In order to explore the transcriptional events downstream these two genes, we will conduct different sets of RNA-seq experiment using neuroblastoma cell line where MEIS1 and SKOR1 will be separately overexpressed or silenced.

We believe such an approach will help us to identify genes that are downstream to MEIS1 and SKOR1, some of which could contribute to the pathogenesis of RLS. Ultimately, more information about the involved pathways could help us to move forward to give these individuals the rest they deserve.