2024-03-29T12:21:05Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1294072020-01-13T11:52:35Zcom_10261_128com_10261_1col_10261_381
DIGITAL.CSIC
author
Spieler, Derek
author
Bessa, José
author
Tena, Juan J.
author
Casares, Fernando
author
Gómez-Skarmeta, José Luis
author
Winkelmann, Juliane
funder
Federal Ministry of Education and Research (Germany)
funder
German Research Center for Environmental Health
funder
German Research Foundation
funder
Israel Science Foundation
funder
German Academic Exchange Service
funder
Technical University of Munich
funder
Fritz Thyssen Foundation
funder
Free State of Bavaria
funder
Munich Center of Health Sciences
funder
Ludwig Maximilians University Munich
funder
Junta de Andalucía
funder
German Center for Diabetes Research
funder
Helmholtz Association
2016-02-24T14:16:39Z
2016-02-24T14:16:39Z
2014
Genome Research 24(4): 592-603 (2014)
http://hdl.handle.net/10261/129407
10.1101/gr.166751.113
http://dx.doi.org/10.13039/501100002347http://dx.doi.org/10.13039/501100001659http://dx.doi.org/10.13039/501100003977http://dx.doi.org/10.13039/501100001655http://dx.doi.org/10.13039/501100005713http://dx.doi.org/10.13039/501100003390http://dx.doi.org/10.13039/501100005722http://dx.doi.org/10.13039/501100001656http://dx.doi.org/10.13039/501100011011
24642863
Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
eng
openAccess
Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon
artículo
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URL
https://digital.csic.es/bitstream/10261/129407/1/Restless%20Legs%20Syndrome.pdf
File
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Restless Legs Syndrome.pdf
URL
https://digital.csic.es/bitstream/10261/129407/5/Restless%20Legs%20Syndrome.pdf.txt
File
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Restless Legs Syndrome.pdf.txt