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.

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Coeur de Montréal Montréal QC Canada

Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum University of Bologna Bologna Italy

Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia Modena Italy

Department of Clinical Neurophysiology and Sleep Center University Lille North of France CHU Lille Lille France

Department of Human Genetics McGill University Montréal QC Canada

Department of Medical Sciences and Public Health Sleep Disorder Research Center University of Cagliari Cagliari Italy

Department of Medicine University of Udine Udine Italy

Department of Neurological Sciences Università Vita Salute San Raffaele Milan Italy

Department of Neurology and Centre of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montréal QC Canada

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Philipps University Marburg Germany

Department of Neurology Sleep Disorders Clinic Medical University of Innsbruck Innsbruck Austria

Department of Neurology St Dimpna Regional Hospital Geel Belgium

Department of Neurology University Hospital Antwerp Edegem Antwerp Belgium

Department of Neurology University Medical Centre Göttingen Göttingen Germany

Department of Neurosciences Clinical Neurology Unit University Hospital of Udine Udine Italy

Department of Neurosciences Neurology Unit Movement Disorders Division Biomedicine and Movement Sciences University of Verona Verona Italy

Department of Neurosciences Université de Montréal Montréal QC Canada

Department of Pharmacology and Therapeutics and Centre de Recherche en Biologie Structurale McGill University Montréal Québec Canada

Department of Psychiatry Université de Montréal Montréal QC Canada

Department of Psychology Université du Québec à Montréal Montréal QC Canada

Department of Sleep Medicine and Neuromuscular Disorders University of Münster Münster Germany

EuroMov University of Montpellier Montpellier France

IRCCS Institute of Neurological Sciences of Bologna Bologna Italy

Laboratory for Sleep Disorders St Dimpna Regional Hospital Geel Belgium

Montreal Neurological Institute McGill University Montréal QC Canada

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

Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

Paracelsus Elena Klinik Kassel Germany

Royal Papworth Hospital NHS Trust Cambridge UK

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France

Sleep disorder Unit Carémeau Hospital University Hospital of Nîmes France

Sleep Disorders Unit Sorbonne University Institut du Cerveau Paris Brain Institute ICM Inserm CNRS AP HP Hôpital de la Pitié Salpêtrière Paris France

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