Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon
- Derek Spieler1,25,
- Maria Kaffe1,2,25,
- Franziska Knauf1,25,
- José Bessa3,
- Juan J. Tena3,
- Florian Giesert4,
- Barbara Schormair1,2,
- Erik Tilch1,2,
- Heekyoung Lee5,6,7,8,
- Marion Horsch9,
- Darina Czamara10,
- Nazanin Karbalai10,
- Christine von Toerne11,
- Melanie Waldenberger12,
- Christian Gieger12,
- Peter Lichtner1,
- Melina Claussnitzer5,6,7,8,24,
- Ronald Naumann13,
- Bertram Müller-Myhsok10,14,15,
- Miguel Torres16,
- Lillian Garrett17,
- Jan Rozman9,7,18,
- Martin Klingenspor5,6,9,18,
- Valérie Gailus-Durner9,
- Helmut Fuchs9,
- Martin Hrabě de Angelis9,7,19,
- Johannes Beckers7,9,19,
- Sabine M. Hölter17,
- Thomas Meitinger1,2,14,
- Stefanie M. Hauck7,11,
- Helmut Laumen5,6,7,8,9,
- Wolfgang Wurst4,10,14,17,20,21,
- Fernando Casares3,
- Jose Luis Gómez-Skarmeta3 and
- Juliane Winkelmann1,14,22,23,26
- 1Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 2Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany;
- 3Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Cientificas/Universidad Pablo de Olavide, 41013 Seville, Spain;
- 4Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 5Else Kroener-Fresenius-Centre for Nutritional Medicine, Technische Universität München, 85350 Freising-Weihenstephan, Germany;
- 6ZIEL-Research Centre for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany;
- 7German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany;
- 8Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85350 Freising-Weihenstephan, Germany;
- 9German Mouse Clinic/Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 10Max Planck Institute of Psychiatry, 80804 Munich, Germany;
- 11Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Enviromenteal Health, 85764 Neuherberg, Germany;
- 12Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 13Transgenic Core Facility, Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;
- 14Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany;
- 15University of Liverpool, Institute of Translational Medicine, Liverpool, L69 3GA, United Kingdom;
- 16Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain;
- 17German Mouse Clinic/Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 18Molecular Nutritional Medicine, Technische Universität München Center of Life and Food Sciences, 85354 Weihenstephan, Germany;
- 19Technische Universität München, Experimental Genetics, 85354 Freising, Germany;
- 20Technische Universität München, Developmental Genetics, 85764 Neuherberg, Germany;
- 21Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 80336 Munich, Germany;
- 22Department of Neurology, Technische Universität München, 81675 Munich, Germany;
- 23Department of Neurology and Neurosciences, Stanford Center for Sleep Medicine and Sciences, Stanford University, Palo Alto, California 94304, USA
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.
Footnotes
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↵26 Corresponding author
E-mail winkelmann{at}stanford.edu
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.166751.113.
Freely available online through the Genome Research Open Access option.
- Received September 15, 2013.
- Accepted February 5, 2014.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
