Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon

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 functionin...

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Detalles Bibliográficos
Autores: Spieler, Derek, Kaffe, Maria, Knauf, Franziska, Bessa, José, Tena, Juan J, Giesert, Florian, Schormair, Barbara, Tilch, Erik, Lee, Heekyoung, Horsch, Marion, Czamara, Darina, Karbalai, Nazanin, von Toerne, Christine, Waldenberger, Melanie, Gieger, Christian, Lichtner, Peter, Claussnitzer, Melina, Naumann, Ronald, Müller-Myhsok, Bertram, Torres, Miguel, Garrett, Lillian, Rozman, Jan, Klingenspor, Martin, Gailus-Durner, Valérie, Fuchs, Helmut, Hrabě de Angelis, Martin, Beckers, Johannes, Hölter, Sabine M, Meitinger, Thomas, Hauck, Stefanie M, Laumen, Helmut, Wurst, Wolfgang, Casares, Fernando, Gómez-Skarmeta, Jose Luis, Winkelmann, Juliane
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7347
Acceso en línea:http://hdl.handle.net/20.500.12105/7347
Access Level:acceso abierto
Palabra clave:Alleles
Animals
Basal Ganglia
Disease Models, Animal
Genome-Wide Association Study
Homeodomain Proteins
Introns
Mice
Myeloid Ecotropic Viral Integration Site 1 Protein
Neoplasm Proteins
Polymorphism, Single Nucleotide
Restless Legs Syndrome
Telencephalon
Enhancer Elements, Genetic
Descripción
Sumario: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.

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