Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder

Yuri L Sosero; Eric Yu; Mehrdad A Estiar; Lynne Krohn; Kheireddin Mufti; Uladzislau Rudakou; Jennifer A Ruskey; Farnaz Asayesh; Sandra B Laurent; Dan Spiegelman; Jean-François Trempe; Timothy G Quinnell; Nicholas Oscroft; Isabelle Arnulf; Jacques Y Montplaisir; Jean-François Gagnon; Alex Desautels; Yves Dauvilliers; Gian Luigi Gigli; Mariarosaria Valente; Francesco Janes; Andrea Bernardini; Karel Sonka; David Kemlink; Wolfgang Oertel; Annette Janzen; Giuseppe Plazzi; Elena Antelmi; Francesco Biscarini; 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; Ronald B Postuma; Guy A Rouleau; Abubaker Ibrahim; Ambra Stefani; Birgit Högl; Michele T M Hu; Ziv Gan-Or

doi:10.3233/JPD-212867

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Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder

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Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder

Yuri L Sosero, Eric Yu, Mehrdad A Estiar, Lynne Krohn, Kheireddin Mufti, Uladzislau Rudakou, Jennifer A Ruskey, Farnaz Asayesh, Sandra B Laurent, Dan Spiegelman, …

Journal of Parkinson's disease, Vol.12(1), pp.333-340

01/01/2022

DOI: https://doi.org/10.3233/JPD-212867

PMID: 34690151

Résumé

Glucosylceramidase - genetics

Humans

Parkinson Disease - complications

REM Sleep Behavior Disorder - diagnosis

Saposins - genetics

Synucleinopathies

PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. To examine the role of PSAP mutations in iRBD. We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

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Titre: Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder
Créateurs - sans rôle: Yuri L Sosero - Montreal Neurological Institute, McGill University, Montréal, QC, Canada
Eric Yu - McGill University
Mehrdad A Estiar - McGill University
Lynne Krohn - McGill University
Kheireddin Mufti - McGill University
Uladzislau Rudakou - McGill University
Jennifer A Ruskey - McGill University
Farnaz Asayesh - McGill University
Sandra B Laurent - McGill University
Dan Spiegelman - McGill University
Jean-François Trempe - Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montréal, Québec, Canada
Timothy G Quinnell - Royal Papworth Hospital NHS Trust, Cambridge, UK
Nicholas Oscroft - Royal Papworth Hospital NHS Trust, Cambridge, UK
Isabelle Arnulf - Sleep Disorders Unit, Sorbonne University, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France
Jacques Y Montplaisir - Université de Montréal
Jean-François Gagnon - Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada
Alex Desautels - Université de Montréal
Yves Dauvilliers - Institute for Neurosciences of Montpellier
Gian Luigi Gigli - University of Udine
Mariarosaria Valente - University of Udine
Francesco Janes - Department of Neurosciences, Clinical Neurology Unit, University Hospital of Udine, Udine, Italy
Andrea Bernardini - Department of Neurosciences, Clinical Neurology Unit, University Hospital of Udine, Udine, Italy
Karel Sonka - Charles University
David Kemlink - Charles University
Wolfgang Oertel - Philipps University of Marburg
Annette Janzen - Philipps University of Marburg
Giuseppe Plazzi - Institute of Neurological Sciences
Elena Antelmi - Department of Neurosciences, Neurology Unit, Movement Disorders Division, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
Francesco Biscarini - University of Bologna
Michela Figorilli - University of Cagliari
Monica Puligheddu - University of Cagliari
Brit Mollenhauer - Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany
Claudia Trenkwalder - Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany
Friederike Sixel-Döring - Paracelsus Elena Klinik Kassel
Valérie Cochen De Cock - EuroMov, University of Montpellier, Montpellier, France
Christelle Charley Monaca - Department of Clinical Neurophysiology and Sleep Center, University Lille North of France, CHU Lille, Lille, France
Anna Heidbreder - University of Münster
Luigi Ferini-Strambi - Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy
Femke Dijkstra - Department of Neurology, University Hospital Antwerp, Edegem, Antwerp, Belgium
Mineke Viaene - Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium
Beatriz Abril - Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, France
Bradley F Boeve - Mayo Clinic
Ronald B Postuma - Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada
Guy A Rouleau - McGill University
Abubaker Ibrahim - Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria
Ambra Stefani - Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria
Birgit Högl - Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria
Michele T M Hu - Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
Ziv Gan-Or - Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
Détails de publication: Journal of Parkinson's disease, Vol.12(1), pp.333-340
Note de subvention: Department of Health J-0901 / Parkinson's UK
Identifiants: 99140188809311
Unité académique: Institut des Neurosciences de Montpellier - INM
Langue: English
Type de ressource: Journal article