TY - JOUR
T1 - Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder
AU - Sosero, Yuri L.
AU - Yu, Eric
AU - Estiar, Mehrdad A.
AU - Krohn, Lynne
AU - Mufti, Kheireddin
AU - Rudakou, Uladzislau
AU - Ruskey, Jennifer A.
AU - Asayesh, Farnaz
AU - Laurent, Sandra B.
AU - Spiegelman, Dan
AU - Trempe, Jean François
AU - Quinnell, Timothy G.
AU - Oscroft, Nicholas
AU - Arnulf, Isabelle
AU - Montplaisir, Jacques Y.
AU - Gagnon, Jean François
AU - Desautels, Alex
AU - Dauvilliers, Yves
AU - Gigli, Gian Luigi
AU - Valente, Mariarosaria
AU - Janes, Francesco
AU - Bernardini, Andrea
AU - Sonka, Karel
AU - Kemlink, David
AU - Oertel, Wolfgang
AU - Janzen, Annette
AU - Plazzi, Giuseppe
AU - Antelmi, Elena
AU - Biscarini, Francesco
AU - Figorilli, Michela
AU - Puligheddu, Monica
AU - Mollenhauer, Brit
AU - Trenkwalder, Claudia
AU - Sixel-Döring, Friederike
AU - Cochen De Cock, Valérie
AU - Monaca, Christelle Charley
AU - Heidbreder, Anna
AU - Ferini-Strambi, Luigi
AU - Dijkstra, Femke
AU - Viaene, Mineke
AU - Abril, Beatriz
AU - Boeve, Bradley F.
AU - Postuma, Ronald B.
AU - Rouleau, Guy A.
AU - Ibrahim, Abubaker
AU - Stefani, Ambra
AU - Högl, Birgit
AU - Hu, Michele T.M.
AU - Gan-Or, Ziv
N1 - Publisher Copyright:
© 2022 - IOS Press. All rights reserved.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - GBA
KW - PSAP
KW - Parkinson's disease
KW - REM sleep behavior disorder
KW - genetics
KW - glucocerebrosidase
KW - saposin C
UR - http://www.scopus.com/inward/record.url?scp=85123814221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123814221&partnerID=8YFLogxK
U2 - 10.3233/JPD-212867
DO - 10.3233/JPD-212867
M3 - Article
C2 - 34690151
AN - SCOPUS:85123814221
SN - 1877-7171
VL - 12
SP - 333
EP - 340
JO - Journal of Parkinson's disease
JF - Journal of Parkinson's disease
IS - 1
ER -