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Meis1 – new insights into restless legs syndrome

The restless legs syndrome (RLS) is a neurological disorder which is characterized by an urge to move the legs and uncomfortable sensations in the lower limbs. The symptoms occur only during rest but moving the affected body part provides temporary relief. Patients are therefore forced to stand up and walk, sometimes calling themselves “nightwalkers”. Consequences are severe sleep disturbances, depression, anxiety and increased cardiovascular risk.
GWAS identified common genetic variants within six risk loci. However, how these, each of which only has a small effect, contributed to RLS was unclear. The strongest RLS association signal identified delineates a 32 kb linkage disequilibrium (LD) block in intron 8 of MEIS1 (2p14).

MEIS1 belongs to the TALE family of homeobox transcription factors and is involved in the development and homeostasis of numerous organs and diseases such as leukemia or neuroblastoma (Azcoitia et al. 2005). In the nervous system, multiple expression domains suggest essential roles for MEIS1 (Toresson et al. 2000), however its spatial, temporal and functional involvement in RLS pathogenesis has remained unknown. The identified risk variant alters gene expression because it binds more strongly to the transcription factor CREB1 which may lead to reduced gene expression of MEIS1. Specifically, the authors observed the reduced gene expression 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 analysis of mutant mice (heterozygous Meis1tm1Mtor) in the primary screening of the German Mouse Clinic showed hyperactivity which resembles the human condition of RLS. For example in the Open Field test the total distance travelled and average speed of forward locomotion was significantly increased in heterozygous mutants compared to wildtype mice. Furthermore the average distance travelled within 21 hours showed a trend to be elevated. This is also reflected in an enhanced energy metabolism and oxygen consumption.

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.

Further information: http://www.helmholtz-muenchen.de/en/news/press-releases/2014/press-release/article/23800/index.html

Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon“, Spieler et al., 2014, Genome Research, doi: http://10.1101/gr.166751.11310.1101/gr.166751.113