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Early brain development implicated in Restless Legs Syndrome

(), 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 in 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 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 of the genome, and when introduced into zebrafish and mouse embryos, led to decreased ability of the to activate . Specifically, the authors observed this reduction in the future basal ganglia. “Here we have pinpointed an anatomical region for RLS,” said lead author of the study, Juliane Winkelmann.

Interestingly, the non-coding region only seems 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 MEIS1, 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 to 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 required to unravel the physiological causes of most human diseases,” said co-author Jose Luis Gómez-Skarmeta.

Scientists from Stanford University, Helmholtz Zentrum München, Technische Universität München, Universidad Pablo de Olavide and Consejo Superior de Investigaciones Científicas (CSIC), Max Planck Institute of Psychiatry, and Centro Nacional de Investigaciones Cardiovasculares (CNIC) contributed to this study.

Source

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

Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon, 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, Müller-Myhsok B, Torres M, Garrett L, Rozman J, Klingenspor M, Gailus-Durner V, Fuchs H, Hrab? de Angelis M, Beckers J, Hölter SM, Meitinger T, Hauck SM, Laumen H, Wurst W, Casares F, Gómez-Skarmeta L, Winkelmann J., Genome Res, DOI: 10.1101/gr.166751.113, published online 18 March 2014.

Cold Spring Harbor Laboratory Press