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FB2026_01
,
released March 12, 2026
This report describes combined saposin deficiency, a form of sphingolipidosis; combined saposin deficiency is inherited as an autosomal recessive. The human gene implicated in this disease is prosaposin (PSAP), a precursor of four small nonenzymatic glycoproteins termed 'sphingolipid activator proteins' (SAPs) that assist in the lysosomal hydrolysis of sphingolipids. combined saposin deficiency results in dysfunction of all four of the small SAPs encoded by PSAP. There is a single orthologous gene in Drosophila, Sap-r, for which amorphic and other loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Sap-r is also orthologous to two additional human genes, PSAPL1 and SFTPB.
The human PSAP gene has not been introduced into flies.
Animals homozygous for an amorphic mutation of Dmel\Sap-r exhibit phenotypes typical of spingolipidosis, including an enlarged endolysosomal compartment and sphingolipid accumulation in most larval tissues assessed. They also exhibit reduced viability with ~50% survival to adulthood; survival of some animals to adulthood allowed study of their progressive neurodegeneration and analysis of lipid profiles in younger and older flies. A single genetic interaction has been described for Dmel\Sap-r; see Sap-r gene report.
[updated May 2025 by FlyBase; FBrf0222196]
[COMBINED SAPOSIN DEFICIENCY; PSAPD](https://omim.org/entry/611721)
[PROSAPOSIN; PSAP](https://omim.org/entry/176801)
Lysosomal storage diseases (LSDs) are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. Sphingolipidoses often present as severe, untreatable forms of LSDs with massive sphingolipid and membrane accumulation in lysosomes, neurodegeneration and very short life expectancy (FBrf0235733 and references cited therein).
Prosaposin deficiency, also called combined saposin deficiency, results in death in early infancy. [from MIM:611721; 2017.12.07]
Variants of the PSAP gene that affect only one of the four encoded peptides result in neurologic deterioration of varying severity. [from MIM:611722, MIM:249900, MIM:610539; 2017.12.17]
Combined saposin deficiency is caused by homozygous or compound heterozygous mutation in the PSAP gene. [from MIM:611721; 2017.12.06]
Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities. [NCBI Gene, PSAP; 2017.12.07]
Saposins are low-molecular mass proteins that serve as activators of lysosomal degradation of sphingolipids, a process that involves sequential action of specific hydrolases. [Gene Cards, PSAP: 2017.12.07]
The PSAP gene encodes prosaposin, a precursor of several small nonenzymatic glycoproteins termed 'sphingolipid activator proteins' (SAPs) that assist in the lysosomal hydrolysis of sphingolipids (O'Brien and Kishimoto, 1991; pubmed:2001789). After proteolytic processing of the prosaposin protein, the 4 released polypeptides (designated SAPA through D) are functional activators. [from MIM:176801; 2017.12.07]
Many to one: 3 human to 1 Drosophila; the other human genes are PSAPL1 and SFTPB.
High-scoring ortholog of human PSAP; moderate-scoring ortholog of PSAPL1 and SFTPB (1 Drosophila to 3 human); Dmel\Sap-r shares 23% identity and 40% similarity with human PSAP.