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)
Résumé :
[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 :
Génétique & processus génétiques
Auteur, co-auteur :
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
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
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
Subventionnement (détails) :
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.
Ekbom KA. Restless legs syndrome. Neurology. 1960;10:868–873. doi:10.1212/wnl.10.9.868
Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. 1995;10(5):634–642. doi:10.1002/mds.870100517
Ulfberg J, Nyström B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord. 2001;16(6):1159–1163. doi:10.1002/mds.1209
Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000;160(14):2137–2141. doi:10.1001/archinte.160.14.2137
Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4):283–295. doi:10.1016/j.smrv.2011.05.002
Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study Memory and Morbidity in Augsburg Elderly. Neurology. 2000;54(5):1064–1068. doi:10.1212/wnl.54.5.1064
Schormair B, Zhao C, Bell S, et al.; 23andMe Research Team. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol. 2017;16(11):898–907. doi:10.1016/S1474-4422(17)30327-7
Desai AV, Cherkas LF, Spector TD, Williams AJ. Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study. Twin Res. 2004;7(6):589–595. doi:10.1375/1369052042663841
Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17(8):739–743.
Strang RR. The symptom of restless legs. Med J Aust. 1967;1(24):1211–1213. doi:10.5694/j.1326-5377.1967.tb73929.x
Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164(2):196–202. doi:10.1001/archinte.164.2.196
Szentkiralyi A, Fendrich K, Hoffmann W, Happe S, Berger K. Incidence of restless legs syndrome in two population-based cohort studies in Germany. Sleep Med. 2011;12(9):815–820. doi:10.1016/j.sleep.2011.06.016
Catoire H, Sarayloo F, Mourabit Amari K, et al. A direct interaction between two restless legs syndrome predisposing genes: MEIS1 and SKOR1. Sci Rep. 2018;8(1):12173. doi:10.1038/s41598-018-30665-6
Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39(8):1000–1006. doi:10.1038/ng2099
Cervenka S, Pålhagen SE, Comley RA, et al. Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain. 2006;129(Pt 8):2017–2028. doi:10.1093/ brain/awl163
Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56(2):263–265. doi:10.1212/wnl.56.2.263
Salminen AV, Silvani A, Allen RP, et al.; International Restless Legs Syndrome Study Group (IRLSSG). Consensus guidelines on rodent models of restless legs syndrome. Mov Disord. 2021;36(3):558–569. doi:10.1002/mds.28401
Azcoitia V, Aracil M, Martínez-A C, Torres M. The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol. 2005;280(2):307–320. doi:10.1016/j.ydbio.2005.01.004
Salminen AV, Garrett L, Schormair B, et al.; German Mouse Clinic Consortium. Meis1: effects on motor phenotypes and the sensorimotor system in mice. Dis Model Mech. 2017;10(8):981–991. doi:10.1242/dmm.030080
Lyu S, Xing H, Liu Y, et al. Deficiency of Meis1, a transcriptional regulator, in mice and worms: neurochemical and behavioral characterizations with implications in the restless legs syndrome. J Neurochem. 2020;155(5):522–537. doi:10.1111/jnc.15177
Leon-Sarmiento FE, Peckham E, Leon-Ariza DS, Bara-Jimenez W, Hallett M. Auditory and lower limb tactile prepulse inhibition in primary restless legs syndrome: clues to its pathophysiology. J Clin Neurophysiol. 2015;32(4):369–374. doi:10.1097/ WNP.0000000000000196
Salminen AV, Schormair B, Flachskamm C, et al. Sleep disturbance by pramipexole is modified by Meis1 in mice. J Sleep Res. 2018;27(4):e12557. doi:10.1111/jsr.12557
Salminen AV, Lam DD, Winkelmann J. Role of MEIS1 in restless legs syndrome: from GWAS to functional studies in mice. In: Stefan C and Imad G, eds. Advances in Pharmacology. Vol. 84. Amsterdam: Elsevier; 2019: 175–184. doi:10.1016/bs.apha.2019.03.003
Schulte EC, Kousi M, Tan PL, et al. Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome. Am J Hum Genet. 2014;95(1):85–95. doi:10.1016/j.ajhg.2014.06.005
Wefers B, Wurst W, Kühn R. Gene editing in mouse zygotes using the CRISPR/Cas9 system. In: Saunders TL, ed. Transgenesis. Vol 2631. Methods in Molecular Biology. New York, NY: Springer US; 2023: 207–230. doi:10.1007/978-1-0716-2990-1_8
Fuchs H, Aguilar-Pimentel JA, Amarie OV, et al. Understanding gene functions and disease mechanisms: phenotyping pipelines in the German Mouse Clinic. Behav Brain Res. 2018;352:187–196. doi:10.1016/j.bbr.2017.09.048
Gailus-Durner V, Fuchs H, Becker L, et al. Introducing the German Mouse Clinic: open access platform for standardized phenotyping. Nat Methods. 2005;2(6):403–404. doi:10.1038/nmeth0605-403
Rozman J, Klingenspor M, Hrabě de Angelis M. A review of standardized metabolic phenotyping of animal models. Mamm Genome. 2014;25(9-10):497–507. doi:10.1007/s00335-014-9532-0
Lusk G. Animal calorimetry. J Biol Chem. 1924;59(1):41–42. doi:10.1016/s0021-9258(18)85293-0
Nie Y, Gavin TP, Kuang S. Measurement of resting energy metabolism in mice using Oxymax open circuit indirect calorimeter. Bio Protoc. 2015;5(18):e1602. doi:10.21769/bioprotoc.1602
Bartolucci ML, Berteotti C, Alvente S, et al. Obstructive sleep apneas naturally occur in mice during REM sleep and are highly prevalent in a mouse model of Down syndrome. Neurobiol Dis. 2021;159:105508. doi:10.1016/j.nbd.2021.105508
Eddy NB, Leimbach D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 1953;107(3):385–393.
Mang GM, Nicod J, Emmenegger Y, Donohue KD, O’Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies. Sleep. 2014;37(8):1383–1392. doi:10.5665/sleep.3936
Rathkolb B, Hans W, Prehn C, et al. Clinical chemistry and other laboratory tests on mouse plasma or serum. Curr Protoc Mouse Biol. 2013;3(2):69–100. doi:10.1002/9780470942390.mo130043
Zhang H, Zhang Y, Ren R, et al. Polysomnographic features of idiopathic restless legs syndrome: a systematic review and meta-analysis of 13 sleep parameters and 23 leg movement parameters. J Clin Sleep Med. 2022;18(11):2561–2575. doi:10.5664/ jcsm.10160
DeAndrade MP, Johnson RL, Unger EL, et al. Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet. 2012;21(18):3984–3992. doi:10.1093/hmg/dds221
Whittom S, Dauvilliers Y, Pennestri MH, et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med. 2007;9(1):54–59. doi:10.1016/j.sleep.2007.01.017
Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol. 2010;6(6):337–346. doi:10.1038/nrneurol.2010.55
Xie K, Fuchs H, Scifo E, et al. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice. Nat Commun. 2022;13(1):6830. doi:10.1038/s41467-022-34515-y
Silva GE, Goodwin JL, Vana KD, Vasquez MM, Wilcox PG, Quan SF. Restless legs syndrome, sleep, and quality of life among adolescents and young adults. J Clin Sleep Med. 2014;10(7):779–786. doi:10.5664/jcsm.3872
Schattschneider J, Bode A, Wasner G, Binder A, Deuschl G, Baron R. Idiopathic restless legs syndrome: abnormalities in central somatosensory processing. J Neurol. 2004;251(8):977–982. doi:10.1007/s00415-004-0475-3
Bachmann CG, Rolke R, Scheidt U, et al. Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome. Brain. 2010;133(3):762–770. doi:10.1093/brain/awq026
Happe S, Zeitlhofer J. Abnormal cutaneous thermal thresholds in patients with restless legs syndrome. J Neurol. 2003;250(3):362–365. doi:10.1007/s00415-003-0987-2
Winkelman JW, Gagnon A, Clair AG. Sensory symptoms in restless legs syndrome: the enigma of pain. Sleep Med. 2013;14(10):934–942. doi:10.1016/j.sleep.2013.05.017
Woods S, Basco J, Clemens S. Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of restless legs syndrome. Front Neurol. 2023;14:1160028. doi:10.3389/ fneur.2023.1160028
Sarberg M, Josefsson A, Wiréhn A, Svanborg E. Restless legs syndrome during and after pregnancy and its relation to snoring. Acta Obstet Gynecol Scand. 2012;91(7):850–855. doi:10.1111/j.1600-0412.2012.01404.x
