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January 04, 2021ArticleOpen Access

Novel Associations of BST1 and LAMP3 with Rapid Eye Movement Sleep Behavior Disorder

View ORCID ProfileKheireddin Mufti, View ORCID ProfileEric Yu, View ORCID ProfileUladzislau Rudakou, Lynne Krohn, Jennifer A. Ruskey, Farnaz Asayesh, Sandra B. Laurent, Dan Spiegelman, Isabelle Arnulf, Michele T.M. Hu, Jacques Y. Montplaisir, Jean-François Gagnon, Alex Desautels, Yves Dauvilliers, Gian Luigi Gigli, Mariarosaria Valente, Francesco Janes, Andrea Bernardini, Birgit Högl, View ORCID ProfileAmbra Stefani, Evi Holzknecht, Karel Sonka, View ORCID ProfileDavid Kemlink, View ORCID ProfileWolfgang Oertel, Annette Janzen, Giuseppe Plazzi, Elena Antelmi, Michela Figorilli, Monica Puligheddu, Brit Mollenhauer, Claudia Trenkwalder, Friederike Sixel-Döring, Valérie Cochen De Cock, Christelle Charley Monaca, Anna Heidbreder, Luigi Ferini-Strambi, Femke Dijkstra, Mineke Viaene, Beatriz Abril, Bradley F. Boeve, Jean-François Trempe, Guy A. Rouleau, Ronald B. Postuma, Ziv Gan-Or
First published January 4, 2021, DOI: https://doi.org/10.1212/WNL.0000000000011464
Kheireddin Mufti
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
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  • ORCID record for Kheireddin Mufti
Eric Yu
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
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Uladzislau Rudakou
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
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Lynne Krohn
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
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Jennifer A. Ruskey
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Farnaz Asayesh
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Sandra B. Laurent
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Dan Spiegelman
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Isabelle Arnulf
4Sleep Disorders Unit, Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, Paris, France.
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Michele T.M. Hu
5Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, United Kingdom.
6Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
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Jacques Y. Montplaisir
7Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’Île-de-Montréal – Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
8Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
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Jean-François Gagnon
7Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’Île-de-Montréal – Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
9Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada.
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Alex Desautels
7Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’Île-de-Montréal – Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
10Department of Neurosciences, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
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Yves Dauvilliers
11National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France.
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Gian Luigi Gigli
12Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
13DMIF, University of Udine, Udine, Italy.
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Mariarosaria Valente
12Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
14Department of Medicine (DAME), University of Udine, Udine, Italy.
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Francesco Janes
12Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
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Andrea Bernardini
12Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
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Birgit Högl
15Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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Ambra Stefani
15Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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Evi Holzknecht
15Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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Karel Sonka
16Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
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David Kemlink
16Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
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Wolfgang Oertel
17Department of Neurology, Philipps University, Marburg, Germany.
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Annette Janzen
17Department of Neurology, Philipps University, Marburg, Germany.
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Giuseppe Plazzi
18Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
19IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
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Elena Antelmi
20Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
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Michela Figorilli
21Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
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Monica Puligheddu
21Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
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Brit Mollenhauer
22Paracelsus-Elena-Klinik, Kassel, Germany.
23Department of Neurosurgery, University Medical Centre Göttingen, Göttingen, Germany.
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Claudia Trenkwalder
22Paracelsus-Elena-Klinik, Kassel, Germany.
23Department of Neurosurgery, University Medical Centre Göttingen, Göttingen, Germany.
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Friederike Sixel-Döring
17Department of Neurology, Philipps University, Marburg, Germany.
22Paracelsus-Elena-Klinik, Kassel, Germany.
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Valérie Cochen De Cock
24Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
25EuroMov Digital Health in Motion, University of Montpellier IMT Mines Ales, Montpellier, France.
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Christelle Charley Monaca
26University Lille North of France, Department of Clinical Neurophysiology and Sleep Center, CHU Lille, Lille, France.
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Anna Heidbreder
27Department of Sleep Medicine and Neuromuscular Disorders, University of Müenster, Müenster, Germany.
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Luigi Ferini-Strambi
28Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
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Femke Dijkstra
29Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
30Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
31Department of Neurology, University Hospital Antwerp, Edegem, Antwerp, Belgium.
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Mineke Viaene
29Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
30Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
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Beatriz Abril
32Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, France.
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Bradley F. Boeve
33Department of Neurology, Mayo Clinic, Rochester, MN, USA.
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Jean-François Trempe
34Centre de Recherche en Biologie Structurale and Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
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Guy A. Rouleau
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Ronald B. Postuma
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
7Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’Île-de-Montréal – Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
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Ziv Gan-Or
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
2Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
3Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
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Full PDF
Citation
Novel Associations of BST1 and LAMP3 with Rapid Eye Movement Sleep Behavior Disorder
Kheireddin Mufti, Eric Yu, Uladzislau Rudakou, Lynne Krohn, Jennifer A. Ruskey, Farnaz Asayesh, Sandra B. Laurent, Dan Spiegelman, Isabelle Arnulf, Michele T.M. Hu, Jacques Y. Montplaisir, Jean-François Gagnon, Alex Desautels, Yves Dauvilliers, Gian Luigi Gigli, Mariarosaria Valente, Francesco Janes, Andrea Bernardini, Birgit Högl, Ambra Stefani, Evi Holzknecht, Karel Sonka, David Kemlink, Wolfgang Oertel, Annette Janzen, Giuseppe Plazzi, Elena Antelmi, Michela Figorilli, Monica Puligheddu, Brit Mollenhauer, Claudia Trenkwalder, Friederike Sixel-Döring, Valérie Cochen De Cock, Christelle Charley Monaca, Anna Heidbreder, Luigi Ferini-Strambi, Femke Dijkstra, Mineke Viaene, Beatriz Abril, Bradley F. Boeve, Jean-François Trempe, Guy A. Rouleau, Ronald B. Postuma, Ziv Gan-Or
Neurology Jan 2021, 10.1212/WNL.0000000000011464; DOI: 10.1212/WNL.0000000000011464

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Abstract

Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD, in a total of 1,039 iRBD patients and 1,852 controls. The role of rare heterozygous variants in these genes was examined using burden tests. The contribution of biallelic variants was further tested. To examine the potential impact of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.

Results: We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in 22 (1.2%) controls vs. two (0.2%) patients. All three variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare non-coding heterozygous variants in LAMP3 were also associated with iRBD (p=0.0006 at >30X). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.

Conclusion: Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.

  • Received July 23, 2020.
  • Accepted in final form December 2, 2020.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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