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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.* ; von Toerne, C. ; 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. ; Hrabě de Angelis, M. ; Beckers, J. ; Hölter, S.M. ; Meitinger, T. ; Hauck, S.M. ; Laumen, H. ; Wurst, W. ; Casares, F.* ; Gómez-Skarmeta, J.L.* ; Winkelmann, J.

Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon.

Genome Res. 24, 592-603 (2014)
Verlagsversion Volltext DOI PMC
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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Transcription Factor-binding; Genome-wide Association; Chromatin Interactions; Noncoding Sequences; Motor Restlessness; Label-free; Dna; Disease; Visualization; Conservation
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 1088-9051
e-ISSN 1549-5469
Zeitschrift Genome Research
Quellenangaben Band: 24, Heft: 4, Seiten: 592-603 Artikelnummer: , Supplement: ,
Verlag Cold Spring Harbor Laboratory Press
Verlagsort Cold Spring Harbor
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Experimental Genetics (IEG)
CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)
Institute of Developmental Genetics (IDG)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30201 - Metabolic Health
90000 - German Center for Diabetes Research
30502 - Diabetes: Pathophysiology, Prevention and Therapy
30204 - Cell Programming and Repair
30203 - Molecular Targets and Therapies
30202 - Environmental Health
Forschungsfeld(er) Genetics and Epidemiology
Enabling and Novel Technologies
PSP-Element(e) G-500700-001
G-500600-001
G-500600-003
G-500600-004
G-501900-063
G-501900-066
G-521600-002
G-500500-001
G-500500-005
G-505700-001
G-504091-001
G-504100-001
G-500500-003
PubMed ID 24642863
DOI 10.1101/gr.166751.113
WOS ID WOS:000334055600006
Erfassungsdatum 2014-03-19
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