MEIS1 p.R272H in familial restless legs syndrome.
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ABSTRACT:
SUBMITTER: Vilarino-Guell C
PROVIDER: S-EPMC2715576 | biostudies-literature | 2009 Jul
REPOSITORIES: biostudies-literature
Publications
MEIS1 p.R272H in familial restless legs syndrome.
Vilariño-Güell C C Chai H H Keeling B H BH Young J E JE Rajput A A Lynch T T Aasly J O JO Uitti R J RJ Wszolek Z K ZK Farrer M J MJ Lin S-C SC
Neurology 20090701 3
Similar Datasets
Project description: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.
| S-EPMC6736557 | biostudies-literature
Project description:Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.
| S-EPMC5397858 | biostudies-literature
Project description:Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the first large scale genome wide association study (GWAS) identified three genomic regions associated with RLS. MEIS1, BTBD9 and MAP2K5/SKOR1 are the only known genes located within these loci and their association with RLS was subsequently confirmed in a number of follow up GWAS. Following this finding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the effect of the risk variants of the three other genes strongly associated with RLS. While these variants had no effect on the mRNA levels of the genes harboring them, we find that the homeobox transcription factor MEIS1 positively regulates the expression of the transcription co-repressor SKOR1. This regulation appears mediated through the binding of MEIS1 at two specific sites located in the SKOR1 promoter region and is modified by an RLS associated SNP in the promoter region of the gene. Our findings directly link MEIS1 and SKOR1, two significantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS.
| S-EPMC6093889 | biostudies-literature
Project description:Genome-wide association studies (GWASs) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and the functional relevance have remained to be elucidated. The MEIS1 locus contains an exceptionally large number of highly conserved non-coding regions (HCNRs), which potentially function as cis-regulatory modules. We analyzed the HCNRs in the RLS-associated linkage disequilibrium (LD) block for allele-dependent enhancer activity in both zebrafish and mouse, comparing the protective and risk alleles of RLS-associated common variants. We found one enhancer, harboring the lead SNP rs12469063, which showed an allele-dependent reduction of reporter gene expression exclusively in the embryonic ganglionic eminences at developmental stage E12.5. Notably, the reporter activity overlapped with the endogenous telencephalic Meis1 expression domain, which co-localized with transcripts of all four validated RLS loci. Thus, the developing telencephalon represents the first neuroanatomic region implicated for RLS based on GWAS findings.
2014-01-29 | GSE44592 | GEO
Project description:Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable or unpleasant sensations in the legs during rest periods. To relieve these sensations, patients move their legs, causing sleep disruption. While the pathogenesis of RLS has yet to be resolved, there is a strong genetic association with the MEIS1 gene. A missense variant in MEIS1 is enriched sevenfold in people with RLS compared to non-affected individuals. We generated a mouse line carrying this mutation (p.Arg272His/c.815G>A), referred to herein as Meis1R272H/R272H (Meis1 point mutation), to determine whether it would phenotypically resemble RLS. As women are more prone to RLS, driven partly by an increased risk of developing RLS during pregnancy, we focused on female homozygous mice. We evaluated RLS-related outcomes, particularly sensorimotor behavior and sleep, in young and aged mice. Compared to noncarrier littermates, homozygous mice displayed very few differences. Significant hyperactivity occurred before the lights-on (rest) period in aged female mice, reflecting the age-dependent incidence of RLS. Sensory experiments involving tactile feedback (rotarod, wheel running, and hotplate) were only marginally different. Overall, RLS-like phenomena were not recapitulated except for the increased wake activity prior to rest. This is likely due to the focus on young mice. Nevertheless, the Meis1R272H mouse line is a potentially useful RLS model, carrying a clinically relevant variant and showing an age-dependent phenotype.
| S-EPMC11502956 | biostudies-literature
Project description:Study objectivesRecent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS.Design setting and participantsDNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci.Measurements and resultsA significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters.ConclusionsOur results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.
| S-EPMC3825427 | biostudies-literature
Project description:Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
| S-EPMC3975059 | biostudies-literature
Project description:Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs at night, which is often accompanied by unpleasant sensations. A recent genomewide association study identified an association between RLS and intronic markers from the MEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish. We carried out a series of experiments to delineate the role of MEIS1 in RLS pathogenesis and the underlying genetic mechanism. We sequenced all 13 MEIS1 exons and their splice junctions in 285 RLS probands with confirmed clinical diagnosis and did not identify any causative coding or exon-intron junction mutations. We found no evidence of structural variation or disease-associated haplotype differential splicing. However, sequencing of conserved regions of MEIS1 introns 8 and 9 identified a novel single nucleotide polymorphism (C13B_2) significantly associated with RLS (allelic association, P = 1.81E-07). We detected a significant decrease in MEIS1 mRNA expression by quantitative real-time polymerase chain reaction in lymphoblastoid cell lines (LCLs) and brain tissues from RLS patients homozygous for the intronic RLS risk haplotype, compared with those homozygous for the non-risk haplotype. Finally, we found significantly decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. Therefore, these data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS.
| S-EPMC2722232 | biostudies-literature
Project description:A link between restless legs syndrome (RLS) and iron has been recognized for several decades. Yet, the precise role that iron or other components of iron metabolism play in bringing about RLS is still a matter of debate. During the last few years, many new pieces of evidence from genetics, pathology, imaging, and clinical studies have surfaced. However, the way this evidence fits into the larger picture of RLS as a disease is not always easily understood. To provide a better understanding of the complex interplay between iron metabolism and RLS and highlight areas that need further elucidation, we systematically and critically review the current literature on the role of iron in RLS pathophysiology and treatment with a special emphasis on genetics, neuropathology, cell and animal models, imaging studies, and therapy.
| S-EPMC6183309 | biostudies-literature