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

Article type: Research Article

Authors: Sosero, Yuri L.^{a; b} | Yu, Eric^{a; b} | Estiar, Mehrdad A.^{a; b} | Krohn, Lynne^{a; b} | Mufti, Kheireddin^{a; b} | Rudakou, Uladzislau^{a; b} | Ruskey, Jennifer A.^{b; c} | Asayesh, Farnaz^{b; c} | Laurent, Sandra B.^{b; c} | Spiegelman, Dan^{b; c} | Trempe, Jean-François^d | Quinnell, Timothy G.^e | Oscroft, Nicholas^e | Arnulf, Isabelle^f | Montplaisir, Jacques Y.^{g; h} | Gagnon, Jean-François^{g; i} | Desautels, Alex^{g; j} | Dauvilliers, Yves^k | Gigli, Gian Luigi^{l; m} | Valente, Mariarosaria^{l; m} | Janes, Francesco^l | Bernardini, Andrea^l | Sonka, Karelⁿ | Kemlink, Davidⁿ | Oertel, Wolfgang^o | Janzen, Annette^o | Plazzi, Giuseppe^{p; q} | Antelmi, Elena^{q; r} | Biscarini, Francesco^s | Figorilli, Michela^t | Puligheddu, Monica^t | Mollenhauer, Brit^{u; v} | Trenkwalder, Claudia^{u; v} | Sixel-Döring, Friederike^{o; u} | Cochen De Cock, Valérie^{w; x} | Monaca, Christelle Charley^y | Heidbreder, Anna^z | Ferini-Strambi, Luigi^aa | Dijkstra, Femke^{bb; cc; dd} | Viaene, Mineke^{bb; cc} | Abril, Beatriz^ee | Boeve, Bradley F.^ff | Postuma, Ronald B.^{b; c; g} | Rouleau, Guy A.^{a; b; c} | Ibrahim, Abubaker^gg | Stefani, Ambra^gg | Högl, Birgit^gg | Hu, Michele T.M.^{hh; ii} | Gan-Or, Ziv^{a; b; c; *}

Affiliations: [a] Department of Human Genetics, McGill University, Montréal, QC, Canada | [b] Montreal Neurological Institute, McGill University, Montréal, QC, Canada | [c] Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada | [d] Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montréal, Québec, Canada | [e] Royal Papworth Hospital NHS Trust, Cambridge, UK | [f] Sleep Disorders Unit, Sorbonne University, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France | [g] Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada | [h] Department of Psychiatry, Université de Montréal, Montréal, QC, Canada | [i] Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada | [j] Department of Neurosciences, Université de Montréal, Montréal, QC, Canada | [k] National Reference Centre for Orphan Diseases, Narcolepsy- Rare hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, Institute for Neurosciences of Montpellier INM, Univ Montpellier, INSERM, Montpellier, France | [l] Department of Neurosciences, Clinical Neurology Unit, University Hospital of Udine, Udine, Italy | [m] Department of Medicine (DAME), University of Udine, Udine, Italy | [n] Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic | [o] Department of Neurology, Philipps University, Marburg, Germany | [p] Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy | [q] IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy | [r] Department of Neurosciences, Neurology Unit, Movement Disorders Division, Biomedicine and Movement Sciences, University of Verona, Verona, Italy | [s] Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy | [t] Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy | [u] Paracelsus-Elena-Klinik, Kassel, Germany | [v] Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany | [w] Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France | [w] EuroMov, University of Montpellier, Montpellier, France | [y] Department of Clinical Neurophysiology and Sleep Center, University Lille North of France, CHU Lille, Lille, France | [y] Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany | [aa] Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy | [bb] Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium | [cc] Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium | [dd] Department of Neurology, University Hospital Antwerp, Edegem, Antwerp, Belgium | [ee] Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, France | [ff] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [gg] Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria | [hh] Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany | [ii] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Correspondence: [*] Correspondence to: Ziv Gan-Or, MD, PhD, Montreal Neurological Institute, McGill University, 1033 Pine Avenue, West, Ludmer Pavilion, room 312, Montréal, QC, H3A 1A1, Canada. Tel.:+1 514 398 5845; E-mail: [email protected].

Abstract: Background: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. Objective:To examine the role of PSAP mutations in iRBD. Methods: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). Results: 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. Conclusion:These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

Keywords: REM sleep behavior disorder, PSAP, saposin C, Parkinson’s disease, GBA, glucocerebrosidase, genetics

DOI: 10.3233/JPD-212867

Journal: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 333-340, 2022