Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder - Sorbonne Université Access content directly
Journal Articles Journal of Parkinson's disease Year : 2022

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

Yuri Sosero
  • Function : Author
Eric Yu
  • Function : Author
Mehrdad Estiar
  • Function : Author
Lynne Krohn
  • Function : Author
Kheireddin Mufti
  • Function : Author
Uladzislau Rudakou
  • Function : Author
Jennifer Ruskey
  • Function : Author
Farnaz Asayesh
  • Function : Author
Sandra Laurent
  • Function : Author
Dan Spiegelman
  • Function : Author
Jean-François Trempe
  • Function : Author
Timothy Quinnell
  • Function : Author
Nicholas Oscroft
  • Function : Author
Jacques Montplaisir
  • Function : Author
Jean-François Gagnon
  • Function : Author
Alex Desautels
  • Function : Author
Yves Dauvilliers
  • Function : Author
Gian Luigi Gigli
  • Function : Author
Mariarosaria Valente
  • Function : Author
Francesco Janes
  • Function : Author
Andrea Bernardini
  • Function : Author
Karel Sonka
  • Function : Author
David Kemlink
  • Function : Author
Wolfgang Oertel
  • Function : Author
Annette Janzen
  • Function : Author
Giuseppe Plazzi
  • Function : Author
Elena Antelmi
  • Function : Author
Francesco Biscarini
  • Function : Author
Michela Figorilli
  • Function : Author
Monica Puligheddu
  • Function : Author
Brit Mollenhauer
  • Function : Author
Claudia Trenkwalder
  • Function : Author
Friederike Sixel-Döring
  • Function : Author
Valérie Cochen de Cock
  • Function : Author
Christelle Charley Monaca
  • Function : Author
Anna Heidbreder
  • Function : Author
Luigi Ferini-Strambi
  • Function : Author
Femke Dijkstra
  • Function : Author
Mineke Viaene
  • Function : Author
Beatriz Abril
  • Function : Author
Bradley Boeve
  • Function : Author
Ronald Postuma
  • Function : Author
Guy Rouleau
  • Function : Author
Abubaker Ibrahim
  • Function : Author
Ambra Stefani
  • Function : Author
Birgit Högl
  • Function : Author
Michele Hu
  • Function : Author
Ziv Gan-Or
  • Function : Author
Michele T.M. Hu
  • Function : Author

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.

Dates and versions

hal-04588870 , version 1 (27-05-2024)

Identifiers

Cite

Yuri Sosero, Eric Yu, Mehrdad Estiar, Lynne Krohn, Kheireddin Mufti, et al.. Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder. Journal of Parkinson's disease, 2022, 12 (1), pp.333-340. ⟨10.3233/JPD-212867⟩. ⟨hal-04588870⟩
0 View
0 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More