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

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 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.

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

“…At our sample size, we are not powered to detect the PD BAG3 association or determine the true causal signal at this locus. Additionally, rare loss-of-function variants in PSAP, which encodes a co-activator of GCase (saposin C), are associated with risk for iRBD 46 . Rare mutations in the PSAP saposin D domain may also be associated with autosomal dominant PD 47 , and a role for common PSAP variants in PD susceptibility is debated 47,48 .…”

Rapid eye movement sleep behaviour disorder: Past, present, and future

“…A similar pattern is found between RBD and DLB, where ALP genes SNCA , GBA , and TMEM175 are shared risk factors in both conditions, however, DLB genes APOE and BIN1 (Chia et al, 2021) are not associated with RBD (Gan‐Or et al, 2017; Krohn et al, 2021). Mutations in PSAP , encoding for saposin C, a lysosomal activator of GBA , have also been implicated in iRBD (Sosero et al, 2022), as well as rare variants in LAMP3 (encoding the lysosomal associated membrane protein 3) and other genes (Mufti, Yu, et al, 2021b). Overall, the shared loci across RBD and overt α‐synucleinopathies are localised in the ALP, and genes associated with other neurodegenerative mechanisms (e.g., tau aggregation, mitochondrial dysfunction) do not appear to play a major role in RBD susceptibility.…”