Objective: To investigate the role of the PSAP gene in PD patients in Taiwan, including familial PD and early-onset Parkinson’s disease.

Background: Mutations in the saposin D domain of prosaposin gene (PSAP), a sphingolipid activator affecting lysosomal function, have been identified in familial Parkinson’s disease (PD). Two intronic variants (rs4747203, T>C, and rs885828, C>T) around saposin D domain were also significantly correlated with increased risk of sporadic PD (SPD). However, the studies on the effect of PSAP variants in PD risk have conflicting results.

Method: Patients of FPD with autosomal dominant (AD) and recessive inheritance (AR), and patients of EOPD with the age of onset less than 50 years old were enrolled at the National Taiwan University Hospital. The whole length of PSAP exons and introns was examined by Sanger sequencing. The allele frequency of rs885828 and rs4747203 between patients and healthy controls (HC) from Taiwan biobank was analyzed using the chi-squared test.

Results: Total 480 patients, including 184 FPD (118 AD, 66 AR) and 296 EOPD were enrolled. Exon sequencing were done in all patients and two novel exonic variants (p.A146E and p.Y248C) were identified. In the analysis of rs885828 and rs4747203, the allelic frequency intronic variants were significantly lower in overall PD group than HC (rs885828, p < 0.001, Odds ratio (OR) = 0.0045, 95% confidence interval (CI) = 0.002-0.011]; rs4747203, p < 0.001, OR = 0.03, 95% CI = 0.077-0.14).  The protective effects are also shown in both dominant and recessive inheritance model. (Table)

Conclusion: Two intronic variants in PSAP are associated with a protective effect in FPD and EOPD, indicating a more universal role of PSAP in the pathogenesis of PD other than sporadic cases. Further large-scale association studies and lysosomal functional studies are warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/polymorphisms-in-prosaposin-gene-are-associated-with-familial-and-early-onset-parkinsons-disease-a-case-control-association-study-and-meta-analysis/