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Genome ResearchVolume 24, Issue 4, April 2014, Pages 592-603

Restless Legs Syndrome-Associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon(Article)(Open Access)

  • Spieler, D.,
  • Kaffe, M.,
  • Knauf, F.,
  • Bessa, J.,
  • Tena, J.J.,
  • Giesert, F.,
  • Schormair, B.,
  • Tilch, E.,
  • Lee, H.,
  • Horsch, M.,
  • Czamara, D.,
  • Karbalai, N.,
  • Toerne, C.V.,
  • Waldenberger, M.,
  • Gieger, C.,
  • Lichtner, P.,
  • Claussnitzer, M.,
  • Naumann, R.,
  • Müller-Myhsok, B.,
  • Torres, M.,
  • Garrett, L.,
  • Rozman, J.,
  • Klingenspor, M.,
  • Gailus-Durner, V.,
  • Fuchs, H.,
  • De Angelis, M.H.,
  • Beckers, J.,
  • Hölter, S.M.,
  • Meitinger, T.,
  • Hauck, S.M.,
  • Laumen, H.,
  • Wurst, W.,
  • Casares, F.,
  • Gómez-Skarmeta, J.L.,
  • Winkelmann, J.
  • View Correspondence (jump link)
  • Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA 02131, United States

Abstract

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. ©2014 Spieler et al.

Indexed keywords

EMTREE drug terms:cyclic AMP responsive element binding proteinMEIS1 proteintranscription factorunclassified drughomeodomain proteinmyeloid ecotropic viral integration site 1 proteintumor protein
EMTREE medical terms:alleleanimal experimentanimal modelarticlebasal ganglionbrain developmentcontrolled studyDNA protein complexeffect sizefemalegene locusgene targetinggenetic associationgenetic riskgenetic variabilityhigh resolution melting analysisin vitro studyintronmalemotor performancemousenonhumanopen field testphenotypepriority journalrestless legs syndromesingle nucleotide polymorphismtelencephalonzebra fishanimaldisease modelenhancer regiongeneticsgrowth, development and agingmetabolismpathologyrestless legs syndrometelencephalon
MeSH:AllelesAnimalsBasal GangliaDisease Models, AnimalEnhancer Elements, GeneticGenome-Wide Association StudyHomeodomain ProteinsIntronsMiceNeoplasm ProteinsPolymorphism, Single NucleotideRestless Legs SyndromeTelencephalon

Chemicals and CAS Registry Numbers:

cyclic AMP responsive element binding protein, 130428-87-4, 130939-96-7;

Homeodomain Proteins; myeloid ecotropic viral integration site 1 protein; Neoplasm Proteins

Funding details

Funding sponsor Funding number Acronym
German Academic Exchange Service0811963DAAD
Massachusetts Department of Fish and GameWI 1820/4-1;DFG
  • ISSN: 10889051
  • CODEN: GEREF
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1101/gr.166751.113
  • PubMed ID: 24642863
  • Document Type: Article
  • Publisher: Cold Spring Harbor Laboratory Press

  Winkelmann, J.; Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, United States;
© Copyright 2014 Elsevier B.V., All rights reserved.

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