title: Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon.
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.
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
authors.forename: Derek
authors.initials: D
authors.lastname: Spieler
authors.forename: Maria
authors.initials: M
authors.lastname: Kaffe
authors.forename: Franziska
authors.initials: F
authors.lastname: Knauf
authors.forename: José
authors.initials: J
authors.lastname: Bessa
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Tena
authors.forename: Florian
authors.initials: F
authors.lastname: Giesert
authors.forename: Barbara
authors.initials: B
authors.lastname: Schormair
authors.forename: Erik
authors.initials: E
authors.lastname: Tilch
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
authors.forename: Christine
authors.initials: C
authors.lastname: von Toerne
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Melina
authors.initials: M
authors.lastname: Claussnitzer
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Miguel
authors.initials: M
authors.lastname: Torres
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.forename: Helmut
authors.initials: H
authors.lastname: Laumen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000483:Alleles; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D007438:Introns; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012148:Restless Legs Syndrome / Q000235:genetics*; D013687:Telencephalon / Q000254:growth & development* / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins