Meis1 effects on motor phenotypes and the sensorimotor system in mice (original) (raw)
Related papers
A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1
Scientific reports, 2018
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 i...
Human Molecular Genetics, 2009
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 5 1.81E207). 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.
Reassessing GWAS findings for the shared genetic basis of insomnia and restless legs syndrome
Sleep, 2018
Two genome-wide association studies (GWAS) suggest that insomnia and restless legs syndrome (RLS) share a common genetic basis. While the identified genetic variation in the MEIS1 gene was previously associated with RLS, the two GWAS suggest a novel and independent association with insomnia symptoms. To test the potential pleiotropic effect of MEIS1, we genotyped three MEIS1 variants in 646 chronic insomnia disorder (CID) patients with and without RLS. To confirm our results, we compared the allelic and genotypic distributions of the CID cohort with ethnically matched controls and RLS cases in the French Canadian cohort. The CID cohort was diagnosed by sleep medicine specialists and 26% of the sample received the combined diagnosis of CID+RLS. We find significant differences in allele and genotype distributions between CID-only and CID+RLS groups, suggesting that MEIS1 is only associated with RLS. Genotype distributions and minor allele frequencies of the three MEIS1 SNPs of the CID-only and control groups were similar (rs113851554: 5.3% vs. 5.6%; rs2300478: 25.3% vs. 26.5%; rs12469063: 23.6% vs. 24.4%; all p > 0.05). Likewise, there were no differences between CID+RLS and RLS-only groups (all p > 0.05). In conclusion, our data confirms that MEIS1 is a genetic risk factor for the development of RLS, but it does not support the pleiotropic effect of MEIS1 in CID. While a lack of power precluded us from refuting small pleiotropic effects, our findings emphasize the critical importance of isolating CID from other disorders that can cause sleep difficulties, particularly RLS, for future genetic studies.
Variant screening of the coding regions of MEIS1 in patients with restless legs syndrome
Neurology, 2011
VARIANT SCREENING OF THE CODING REGIONS OF MEIS1 IN PATIENTS WITH RESTLESS LEGS SYNDROME Restless legs syndrome (RLS) is a common and genetically complex neurologic disease presenting with an urge to move the legs and dysesthesias in the evening and at times of rest. Genome-wide association studies have linked single nucleotide polymorphisms in MEIS1 and 3 other loci to an increased susceptibility to RLS. 1-3 However, to date, only one potentially causal variant has been reported. 4 Therefore, we screened the coding regions and exon-intron boundaries of MEIS1 for variants, which by exerting a strong phenotypic effect could provide a basis for assessing the function of the gene in RLS. Methods. Using Idaho LightScanner high-resolution melting curve analysis, we screened DNA of 188 patients with RLS of a first discovery sample (72.8% female, mean age 60.0 Ϯ 11.2 years), all harboring RLS risk alleles of MEIS1 (G/T or G/G for rs2300478), for aberrant melting patterns (e-Methods on the Neurology ® Web site at www.neurology.org). Exons showing changes suggestive of variants were sequenced on an ABI Prism 3730 sequencer, and variants identified were subsequently genotyped in an independent German sample (henceforth termed "second sample") consisting of 735 patients with RLS (70.8% female, mean age 61.5 Ϯ 14.2 years) and 735 unrelated control subjects (74.5% female, mean age 59.8 Ϯ 11.3 years) by matrixassisted laser desorption ionization/time-of-flight mass spectrometry. Disease segregation was evaluated in one family with the p.R272H mutation of exon 8 of MEIS1, previously related to RLS. 4 RLS in all patients was diagnosed in accordance with standard diagnostic criteria 5 (e-Methods). Standard protocol approvals, registrations, and patient consents. Ethics review board approval and participants' written informed consent were obtained.
MEIS1 p.R272H IN FAMILIAL RESTLESS LEGS SYNDROME
Neurology, 2009
Restless legs syndrome (RLS, OMIM 102300) is a neurologic condition characterized by a distressing urge to move the legs, usually accompanied by an uncomfortable sensation described as a crawling, muscle ache, or tension. It is usually brought on by rest, worse in the evening or night, and relieved by movement. Recently, MEIS1 and BTBD9 have been identified and confirmed as RLS susceptibility genes; however, all the variants found to be associated with disease are located deep in intronic regions and are not thought to be functional. 2-4 To date, sequencing of MEIS1 and BTBD9 in RLS samples has not been reported and therefore functional variants responsible for the increased disease risk have not been identified. Here we report sequencing of all MEIS1 and BTBD9 coding exons and exon-intron boundaries in RLS familial probands followed by assessment of segregation of novel variants with disease within families and evaluation of prevalence in patients with RLS and the general population.
Nature Genetics, 2007
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.
Behavioral and genetic dissection of a mouse model for advanced sleep phase syndrome
Sleep, 2011
The adaptive value of the endogenous circadian clock arises from its ability to synchronize (i.e., entrain) to external light-dark (LD) cycles at an appropriate phase. Studies have suggested that advanced circadian phase alignment might result from shortening of the period length of the clock. Here we explore mechanisms that contribute to an early activity phase in CAST/EiJ (CAST) mice. We investigated circadian rhythms of wheel-running activity in C57BL/6J (B6), CAST and 2 strains of B6.CAST congenic mice, which carry CAST segments introgressed in a B6 genome. When entrained, all CAST mice initiate daily activity several hours earlier than normal mice. This difference could not be explained by alterations in the endogenous period, as activity onset did not correlate with period length. However, the photic phase-shifting responses in these mice were phase-lagged by 3 hours relative to their activity. Attenuated light masking responses were also found in CAST mice, which allow for ac...
Genetics of restless legs syndrome
Parkinsonism & Related Disorders, 2006
Restless legs syndrome (RLS) is a highly familial trait with heritability estimates of about 50%. It is a polygenetic disorder in which a number of variants contribute to the phenotype. Linkage studies in families with RLS revealed several loci but have not yet led to the identification of disease-causing sequence variants. Phenocopies, nonpenetrance, and possible intrafamilial heterogeneity make it difficult to define the exact candidate region. Genome-wide association studies identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/ 5 5 LBOXCOR1 / / . Carriers of one risk allele had a 50% increased risk of developing RLS. MEIS1 and LBXCOR1 are developmental factors and raise new pathophysiologic questions for RLS. These variants have weak and moderate effects and increase the risk of developing RLS. It is still possible that strong effects explain the occurrence of RLS in families. Therefore, linkage and association studies should be used congruently to dissect the complete genetic architecture of RLS.
PLoS Genetics
Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 ...