Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients’ sera in a mouse model of restless legs syndrome

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Abstract

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS.

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Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

Florian Holsboer, Claudia Trenkwalder, Bertram Müller-Myhsok … (2007)

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

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Restless legs syndrome associated with major diseases: A systematic review and new concept.

Claudia Trenkwalder, Richard Allen, Birgit Högl … (2016)

Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a continuous spectrum with a major genetic contribution at one end and a major environmental or comorbid disease contribution at the other.

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A genetic risk factor for periodic limb movements in sleep.

Hreinn Stefansson, David B. Rye, Andrew Hicks … (2007)

The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease. Copyright 2007 Massachusetts Medical Society.

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Author and article information

Contributors

Yuichi Inoue: inoue@somnology.com

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 8 November 2019

Publication date PMC-release: 8 November 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 16344

Affiliations

[1 ]ISNI 0000000123090000, GRID grid.410804.9, Department of Pediatrics, , Jichi Medical University, ; Tochigi, Japan

[2 ]ISNI 0000 0000 9269 4097, GRID grid.256642.1, Department of Pediatrics, , Gunma University Graduate School of Medicine, ; Gunma, Japan

[3 ]ISNI 0000 0001 1092 3579, GRID grid.267335.6, Department of Integrative Physiology, , Institute of Biomedical Sciences, Tokushima University Graduate School, ; Tokushima, Japan

[4 ]ISNI 0000 0001 0663 3325, GRID grid.410793.8, Department of Somnology, , Tokyo Medical University, ; Tokyo, Japan

Author information

Kazuhiro Muramatsu http://orcid.org/0000-0001-9256-5591

Article

Publisher ID: 52735

DOI: 10.1038/s41598-019-52735-z

PMC ID: 6841937

PubMed ID: 31704978

SO-VID: 592f5844-f08d-41f0-bab3-d03bbb6016bc

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 January 2019

Date accepted : 31 July 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100007132, Otsuka Pharmaceutical (Otsuka Pharmaceutical Co., Ltd.);

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ScienceOpen disciplines: Uncategorized

Keywords: neurophysiology,sleep disorders

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ScienceOpen disciplines: Uncategorized

Keywords: neurophysiology, sleep disorders

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Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients’ sera in a mouse model of restless legs syndrome

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Most cited references 23

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

Restless legs syndrome associated with major diseases: A systematic review and new concept.

A genetic risk factor for periodic limb movements in sleep.

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