Early brain development implicated in Restless Legs Syndrome

March 19, 2014

In a study published online in Genome Research, researchers of the Helmholtz Zentrum München und the Technische Universität München have demonstrated that a common genetic variant associated with Restless Legs Syndrome (RLS) alters the expression of a critical gene during fetal development of the brain. This leads to alterations of the developing forebrain indicating an anatomical region involved in RLS.

Restless Legs Syndrome (RLS), a neurological disorder characterized by unpleasant sensations in the legs and the urge to move them, is not caused by a single genetic defect, but rather is a complex disorder influenced by many genetic and environmental components. 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.

MEIS1 gene variant leads to altered development of the brain

In this new study, authors from the Helmholtz Zentrum München (HMGU) and Technische Universität München as well as the Stanford Center for Sleep Medicine and Sciences demonstrate how one of these variants may contribute to RLS. The RLS-associated variant is located in a non-coding region of the MEIS1 gene and led to decreased ability to activate gene expression. Specifically, the authors observed the reduced in the future basal ganglia in the forebrain. "Here we have pinpointed down to an anatomical region for RLS," says lead author of the study, Prof. Juliane Winkelmann from HMGU, who is currently doing research at the Stanford University.

"The RLS-associated variant is located in an intron of MEIS1, a transcription factor involved in organ development and maintenance. The risk variant binds more strongly to the transcriptional regulator CREB1, which may lead to the reduced MEIS1 expression", explains Prof. Dr. Wolfgang Wurst from HMGU. Furthermore, screening analyses in animal models with reduced MEIS1 expression, conducted by the Institute of Experimental Genetics at the HMGU, led by Prof. Dr. Martin Hrabě de Angelis, showed hyperactivity, which resembles the human condition of RLS.

Reduced gene activity predisposition for RLS

Interestingly, the non-coding region only seems to be 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."

In further studies researchers aim to investigate the affected cells in the forebrain. Based on their findings new treatment strategies for RLS may be developed.

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 required to unravel the physiological causes most of human diseases.

Explore further: Restless legs syndrome may signify bigger health problems

More information: D. Spieler, M. Kaffe, F. Knauf, J. Bessa, J. Tena, F. Giesert, B. Schormair, E. Tilch, H. Lee, M. Horsch, D. Czamara, N. Karbalai, C. von Toerne, M. Waldenberger, C. Gieger, P. Lichtner, M. Claussnitzer, R. Naumann, B. Müller-Myhsok, M. Torres, L. Garrett, Jan Rozman, M. Klingenspor, V. Gailus-Durner, H. Fuchs, M. Hrabě de Angelis, J. Beckers, S. M. Hölter, T. Meitinger, S. Hauck, H. Laumen, W. Wurst, F. Casares, J. Gomez-Skarmeta, J. Winkelmann (2014), Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Research, DOI: 10.1101/gr.166751.113

Related Stories

Restless legs syndrome may signify bigger health problems

March 5, 2014
A nationally-recognized sleep expert has published an editorial describing Restless Legs Syndrome (RLS) as a possible biomarker for underlying disease. The editorial appears in the March 5, 2014 issue of Neurology the medical ...

A new gene identified for restless legs syndrome

July 14, 2011
People suffering from restless legs syndrome (RLS) experience unpleasant sensations in the legs at night for which the only remedy is movement. Now, an international consortium from Europe, Canada and the US has identified ...

Men with restless legs syndrome may be at higher risk of early death

June 12, 2013
Men who experience restless legs syndrome (RLS) may have a higher risk of dying earlier, according to research that appears in the June 12, 2013, online issue of Neurology, the medical journal of the American Academy of Neurology. ...

The protein profile of restless leg syndrome

June 6, 2013
A protein profile of people with restless leg syndrome (RLS), identifies factors behind disrupted sleep, cardiovascular dysfunction and pain finds research in BioMed Central's open access journal Fluids and Barriers of the ...

Genetic risk factors for restless legs syndrome identified

August 4, 2011
An international research team has discovered the genetic risk factors for restless legs syndrome (RLS), a disorder that triggers unpleasant sensations in people's legs at night. The study, presented in the journal PLoS Genetics, ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Mar 19, 2014
All patients with symptoms of restless legs syndrome (RLS) should be tested for iron deficiency.[5, 6] At a minimum, a ferritin level should be obtained.

If a common genetic variant associated with Restless Legs Syndrome (RLS) alters the expression of a critical gene during fetal development of the brain, the gene's expression is probably nutrient-dependent and perhaps more specifically linked to iron uptake and perhaps even to a hemoglobin variant associated with glycosylation and thyroxine transport via nutrient-dependent changes in the microRNA/messenger RNA balance.

Biophysical constraints usually prevent such problems but nutritional epigenetics seems a more likely approach than attempting to find a particular gene, which can then be reported in the context of mutation-driven evolution and the practice of medicine.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.