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Early brain development implicated in Restless Legs Syndrome


March 18, 2014 – Restless Legs Syndrome (RLS), a neurological disorder characterized by unpleasant sensations in the legs and the urge move them, affects up to 10% of Americans, although little is known about its cause. In a study published online in Genome Research, researchers have demonstrated a common genetic variant associated with RLS alters expression of a critical brain gene during fetal development.

RLS is not caused by a single genetic defect, but rather is a complex disorder influenced by many genetic and environmental components, with age being the strongest risk factor. Previously, researchers identified genetic variants in RLS patients; however, how these variants, each of which only has a small effect, contributed to RLS was unclear.

In this new study, authors demonstrate how one of these variants may contribute to RLS. The RLS-associated variant is located in a non-coding region of the genome, and when introduced into zebrafish and mouse embryos, led to decreased ability of the non-coding region to activate gene expression. Specifically, the authors observed this reduction in the future basal ganglia. �"Here we have pinpointed down to an anatomical region for RLS," said lead author of the study, Juliane Winkelmann.

Interestingly, the non-coding region seems only active during early brain development, suggesting that RLS, which is associated with aging, may have fetal origins. "Minor alterations in the developing forebrain during early embryonic development are probably leading to a predisposition to RLS," Winkelmann said. "Later in life, during aging, and together with environmental factors, these may lead to the manifestation of the disease."

The RLS-associated variant is located in an intron of , a transcription factor involved in organ development and maintenance.� The future basal ganglia, where the non-coding region is active, is also where MEIS1 is expressed, suggesting the non-coding region could be controlling MEIS1 expression. The risk variant binds more strongly to the transcriptional regulator CREB1, which may lead to the reduced MEIS1 expression. Furthermore, mice with reduced MEIS1 expression display hyperactivity, which resembles the human condition of RLS.�

This study provides one of the first in-depth examinations of a genetic variant identified in a genome-wide association study, which examines many individuals for genetic variants that are linked to a trait. Although many variants are often reported in these studies, it has been difficult understand how variants contribute to disease because they often lie in non-coding regions of the genome and have small effect sizes. "This work also reveals that combinatorial use of multiple approaches will be likely require to unravel the physiological causes most of human diseases," said co-author Jose Luis Gomez-Skarmeta.

Scientists from Stanford University, Helmholtz Zentrum M�nchen, Technische Universit�t M�nchen, Universidad Pablo de Olavide and Consejo Superior de Investigaciones Cient�ficas (CSIC), Max Planck Institute of Psychiatry, and Centro Nacional de Investigaciones Cardiovasculares (CNIC) contributed to this study.

This work was supported by funding from the Fritz Thyssen Stiftung Foundation, German Federal Ministry of Education and Research (BMBF), Technische Universit�t M�nchen (KKF-TUM), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Zentrum M�nchen, Munich Cluster for Systems Neurology (Synergy), and the State of Bavaria, Spanish and Andalusian governments.

Media contacts:

The authors are available for more information by contacting:

Bruce Goldman, Office of Communication & Public Affairs, Stanford School of Medicine (+1-650-725-2106, [email protected]) 

Communication Department, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health (GmbH) (+49-89-3187-2238, [email protected]) 

Klinikum rechts der Isar Technische Universit�t M�nchen Communications Office (+49-089-4140-2046, [email protected]) 

Interested reporters may obtain copies of the manuscript via email from Peggy Calicchia, Administrative Assistant, Genome Research ([email protected], +1-516-422-4012).

About the article:

The manuscript will be published online ahead of print on 18 March 2014. Its full citation is as follows: Spieler D, Kaffe M, Knauf F, Bessa J, Tena JJ, Giesert F, Schormair B, Tilch E, Lee H, Horsch M, Czamara D, Karbalai N, von Toerne C, Waldenberger M, Geiger C, Lichtner P, Claussnitzer M, Naumann R, M�ller-Myhsok B, Torres M, Garrett L, Rozman J, Klingenspor M, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Beckers J, H�lter SM, Meitinger T, Hauck SM, Laumen H, Wurst W, Casares F, G�mez-Skarmeta L, Winkelmann J. Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Res doi: 10.1101/gr.166751.113

About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine.� Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory’s five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Genome Research issues press releases to highlight significant research studies that are published in the journal.

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