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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.


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. Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder. Journal of Parkinson's disease. 2022;12(1):333-340

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PMID: 34690151

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