MEIS1; mouse model; restless legs syndrome; Homeodomain Proteins; MEIS1 protein, human; Meis1 protein, mouse; Myeloid Ecotropic Viral Integration Site 1 Protein; Neoplasm Proteins; Animals; Female; Humans; Mice; Age Factors; Disease Models, Animal; Mice, Inbred C57BL; Mutation, Missense/genetics; Neoplasm Proteins/genetics; Phenotype; Point Mutation/genetics; Sleep/genetics; Sleep/physiology; Homeodomain Proteins/genetics; Myeloid Ecotropic Viral Integration Site 1 Protein/genetics; Restless Legs Syndrome/genetics; Restless Legs Syndrome/physiopathology; Male; Mutation, Missense; Point Mutation; Sleep; Medicine (all)
Abstract :
[en] Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable or unpleasant sensations in the legs during rest periods. To relieve these sensations, patients move their legs, causing sleep disruption. While the pathogenesis of RLS has yet to be resolved, there is a strong genetic association with the MEIS1 gene. A missense variant in MEIS1 is enriched sevenfold in people with RLS compared to non-affected individuals. We generated a mouse line carrying this mutation (p.Arg272His/c.815G>A), referred to herein as Meis1R272H/R272H (Meis1 point mutation), to determine whether it would phenotypically resemble RLS. As women are more prone to RLS, driven partly by an increased risk of developing RLS during pregnancy, we focused on female homozygous mice. We evaluated RLS-related outcomes, particularly sensorimotor behavior and sleep, in young and aged mice. Compared to noncarrier littermates, homozygous mice displayed very few differences. Significant hyperactivity occurred before the lights-on (rest) period in aged female mice, reflecting the age-dependent incidence of RLS. Sensory experiments involving tactile feedback (rotarod, wheel running, and hotplate) were only marginally different. Overall, RLS-like phenomena were not recapitulated except for the increased wake activity prior to rest. This is likely due to the focus on young mice. Nevertheless, the Meis1R272H mouse line is a potentially useful RLS model, carrying a clinically relevant variant and showing an age-dependent phenotype.
Disciplines :
Genetics & genetic processes
Author, co-author :
Leu, Chia-Luen; Institute of Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Lam, Daniel D; Institute of Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
Salminen, Aaro V; Institute of Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
Wefers, Benedikt; Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Becker, Lore; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, Neuherberg, Germany
Garrett, Lillian; Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, Neuherberg, Germany
ROZMAN, Jan ; University of Luxembourg ; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, Neuherberg, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany
Wurst, Wolfgang; Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany ; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Germany ; Chair of Developmental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Hrabě de Angelis, Martin; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, Neuherberg, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany ; Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität, München, Freising, Germany
Hölter, Sabine M ; Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Winkelmann, Juliane; Institute of Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Williams, Rhîannan H ; Institute of Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
External co-authors :
yes
Language :
English
Title :
A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice.
German Federal Ministry of Education and Research German Center for Diabetes Research European Union's Horizon 2020 Research and Innovation Program NIH
Funding text :
This study was supported by internal funding (Helmholtz Munich) to JW; German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012) and German Center for Diabetes Research (DZD) to MHdA; and by the ERC under the European Union\u2019s Horizon 2020 Research and Innovation Program Grant Agreement No. 715933 to RHW.
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