Submission Details

PSAP was first reported in relation to combined PSAP deficiency (MONDO:0012719), an autosomal recessive lysosomal disease, by Schnabel et al in 1992 (PMID: 1371116). Combine PSAP deficiency is a fatal infantile storage disorder, resulting from abnormal accumulation of sphingolipids in body tissues, characterized by severe neurologic disease and hepatosplenomegaly. PSAP encodes prosaposin, a highly conserved glycoprotein which is a precursor for 4 cleavage products, the Sphingolipid Activator Proteins, or saposins A, B, C, and D. Saposins localize primarily to the lysosomes where they each have a different role the catabolism of glycosphingolipids (Meyer et al, 2014, PMID: 25130661). Because the location and type of different variants within PSAP determines which specific saposin is impacted, PSAP will be curated separately for four different conditions: combined PSAP deficiency (this curation), Krabbe disease due to saposin A deficiency, metachromatic leukodystrophy due to saposin B deficiency, and Gaucher disease due to saposin C deficiency. These “splits” in curations were made on the basis of the published disease assertions, molecular mechanism (impact of the variant on the protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines. In this curation, data on 5 variants in PSAP (frameshift, nonsense, splice site, initiator codon) in 6 patients from 5 publications were collected (Schnabel et al, 1992, PMID: 1371116; Hulková et al, 2001, PMID: 11309366; Elleder et al, 2005, PMID: 15944902; Kuchar et al, 2009, PMID: 19267410; Motta et al, 2016, PMID: 26831127). More than the maximum twelve points were collected for genetic evidence. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including the biochemical functional of prosaposin, which is consistent with the biochemical and clinical findings in patients (Henseler et al, 1996, PMID: 8626540; O’Brien et al, 1998; reviewed in Kishimoto et al, 1992, PMID: 1402395), the results of an experiment in which accumulation of ceramide in PSAP-deficient human fibroblast cells was rescued by culturing the cells in medium containing the precursor protein (Henseler et al, 1996, PMID: 8626540), and the clinical and biochemical features observed in a PSAP knock-out mouse (Fujita et al, 1996). Additional evidence is available in the literature, but the maximum points for genetic evidence (6 points) has been reached. In summary, PSAP is definitely associated with autosomal recessive “combined PSAP deficiency”. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 20, 2023, SOP v9.