Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1065-1074; doi:10.1093/hmg/ddn443
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MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels
1 Centre of Excellence in Neuromics of University of Montreal, CHUM Research Centerand Department of Medicine, University of Montreal, Montréal, Québec, H2L 4M1, Canada 2 Research Center, Douglas Hospital, McGill University, Montréal, Québec, H4H 1R3, Canada 3 Department of Neurology, Johns Hopkins University, Baltimore, MD 21224, USA 4 Centre d'Étude du Sommeil, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec, H4J 1C5, Canada
* To whom correspondence should be addressed. Tel: +1 514 890 8000; Fax: +1 514 412 7602; Email: guy.rouleau{at}umontreal.ca
Received October 28, 2008; Revised December 12, 2008; Accepted December 30, 2008
Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs at night, which is often accompanied by unpleasant sensations. A recent genomewide association study identified an association between RLS and intronic markers from the MEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish. We carried out a series of experiments to delineate the role of MEIS1 in RLS pathogenesis and the underlying genetic mechanism. We sequenced all 13 MEIS1 exons and their splice junctions in 285 RLS probands with confirmed clinical diagnosis and did not identify any causative coding or exon–intron junction mutations. We found no evidence of structural variation or disease-associated haplotype differential splicing. However, sequencing of conserved regions of MEIS1 introns 8 and 9 identified a novel single nucleotide polymorphism (C13B_2) significantly associated with RLS (allelic association, P = 1.81E–07). We detected a significant decrease in MEIS1 mRNA expression by quantitative real-time polymerase chain reaction in lymphoblastoid cell lines (LCLs) and brain tissues from RLS patients homozygous for the intronic RLS risk haplotype, compared with those homozygous for the non-risk haplotype. Finally, we found significantly decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. Therefore, these data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS.
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