A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1

Catoire, Hélène; Sarayloo, Faezeh; Amari, Karim Mourabit; Apuzzo, Sergio; Grant, Alanna; Rochefort, Daniel; Xiong, Lan; Montplaisir, Jacques; Earley, Christopher J.; Turecki, Gustavo; Rouleau, Guy A.

doi:10.1038/s41598-018-30665-6

Cited by 24 publications

(27 citation statements)

References 42 publications

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“…Consistent with previous findings 9 , 10 , expression of three previous RLS GWAS genes, MEIS1 in the dorsolateral prefrontal cortex and tibial nerve, SKOR1 in frontal cortex and pituitary, and MAP2K5 in the dorsolateral prefrontal cortex were associated with RLS. Two additional genes, IQCH and SKAP1 , which were not reported in the previous GWAS, were significantly associated with the RLS.…”

Section: Discussionsupporting

confidence: 92%

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Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

et al. 2020

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Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5–15% in Central Europe and North America. Although genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. We conducted a transcriptome-wide association study involving 15,126 RLS cases and 95,725 controls, from the most recent meta-analysis of GWAS, and gene expression weights of GTEx v7 and the CMC dorsolateral prefrontal cortex tissue panels. We identified 13 associations (in 8 independent loci) at the transcriptome-wide significant level, of which 6 were not implicated in the previous GWAS: SKAP1 , SLC36A1 , CCDC57 , FN3KRP , NCOA6 / TRPC4AP . A fine-mapping approach prioritized CMTR1 , RP1-153P14.5 , PRPF6 , and PPP3R1 – to our knowledge, the latter of which is the first RLS-associated gene directly implicated in dopaminergic pathways. Overall, our findings highlight the power of integrating gene expression data with GWAS to prioritize putative causal genes for functional follow-up studies.

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Section: Discussionsupporting

confidence: 92%

“…In the previous RLS GWAS, MEIS1 was identified as the most significant genetic risk factor, motivating subsequent functional studies of this gene 9 , 10 . However, fine-mapping of the corresponding genomic locus prioritized PPP3R1 with a posterior probability of 0.63 in the 90%-credible gene set.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

et al. 2020

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“…Expression studies of the RLS associated loci of BTBD9, MAP2K5 , and SKOR1 (previously called LBXCOR1 ) did not find changes in their levels of expression in lymphoblasts or two brain regions (pons and thalamus) of RLS patients (43). However, RLS patients with the MEIS1 risk haplotype were observed to have a reduced expression of SKOR1 , in addition to a reduced expression of MEIS1 (Figure 1) (43). Follow up studies using siRNA targeting MEIS1 , electromobility shift assays and luciferase reporter assays suggested the expression of SKOR1 to be under the regulatory control of MEIS1.…”

Section: Meis1 Regulates Skor1mentioning

confidence: 95%

“…Follow up studies using siRNA targeting MEIS1 , electromobility shift assays and luciferase reporter assays suggested the expression of SKOR1 to be under the regulatory control of MEIS1. This transcription factor action of MEIS1 is due to its direct binding on two distinct promoter regions of SKOR1 (43). Hence the dysregulation of MEIS1 might predispose to RLS both directly and indirectly, possibly throughout its regulatory role on other genes like SKOR1 .…”

Section: Meis1 Regulates Skor1mentioning

confidence: 99%

MEIS1 and Restless Legs Syndrome: A Comprehensive Review

Sarayloo

Rouleau

2019

Front. Neurol.

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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 MEIS1. The MEIS1 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 C. elegans showed a link between the MEIS1 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 MEIS1 gene identifying an RLS-associated-SNP dependent enhancer activity from the highly conserved non-coding regions (HCNR) of MEIS1. Furthermore, this gene shows a lower expression of mRNA and protein in blood and thalamus of individuals with the MEIS1 RLS risk haplotype. Simulating this reduced MEIS1 expression in mouse models resulted in circadian hyperactivity, a phenotype compatible with RLS. While MEIS1 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 MEIS1 suggest promising links to RLS pathways, however more in-depth studies on this gene's function are required. One important aspect of MEIS1'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.

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“…76 The link between MEIS1and SKOR1 was further elucidated by Catoire et al potentially implicating them in the modulation of pain and sensory input processing of RLS. 77 Interestingly, one study on childhood-onset RLS showed the association with MEIS1 and what is currently referred to as SKOR1, but not with BTBD9. 61 Iron deficiency has been the single best documented biological abnormality for RLS.…”

Section: Genetics and Pathophysiologymentioning

confidence: 99%

Restless Legs Syndrome and Periodic Limb Movement Disorder in Children

Sharon

Walters

Simakajornboon

2019

JCS

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Introduction Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) have been studied more than any other sleep-related movement disorder in the pediatric population. A common feature to both, periodic limb movements, occurs in many other disorders and also in reportedly healthy children and adolescents. In this review, we discuss the different types of limb movements as it pertains to pediatric RLS and PLMD and provides an update on these disorders. Methods A literature search was performed with the following inclusion criteria: English publication, limb movements, leg movements, periodic limb movements of sleep, periodic limb movements during wake, PLMD, RLS, with each of the modifiers, children, pediatric, and adolescents. Identified publications were reviewed and their reference lists were searched for additional relevant publications. Results A total of 102 references were included in this review. These included epidemiological studies, prospective and retrospective studies, case series, observational data, reviews, and consensus guidelines. A critical summary of these findings is presented. Conclusion The limited evidence-based data support the importance of evaluating limb movements in the context of the clinical symptomatology presented by the child or the adolescent. Further research is needed to (1) better understand the pathophysiological mechanisms resulting in periodic limb movements as encountered in the pediatric PLMD or RLS patient and their impact on the overall health and well-being, (2) develop objective diagnostic criteria for RLS and differentiate it from its “mimics” in the pediatric population, and (3) establish evidence-based guidelines for treatment.

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A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1

Cited by 24 publications

References 42 publications

Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

MEIS1 and Restless Legs Syndrome: A Comprehensive Review

Restless Legs Syndrome and Periodic Limb Movement Disorder in Children

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