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PSAP
prosaposin
The PSAP gene encodes prosaposin, a protein essential for the proper breakdown of fatty substances, known as sphingolipids, within cellular lysosomes. Prosaposin acts as a precursor for several smaller proteins called saposins, which are crucial for lysosomal enzyme activity.
PSAP is located on the long (q) arm of chromosome 10, at band 10q22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PSAP gene provides instructions for creating a protein called prosaposin. This protein is fundamental for several biological functions, including the normal development of the nervous system and the reproductive system. Prosaposin is a precursor molecule that is processed into four distinct smaller proteins: saposin A, B, C, and D [PMID:16091807].
These individual saposins are located within lysosomes, which are cellular compartments responsible for recycling waste products. Within lysosomes, saposins collaborate with specific enzymes to break down fatty substances known as sphingolipids. Disruptions in PSAP function can lead to the accumulation of these lipids, causing lysosomal storage disorders [PMID:11707923].
What the gene does
The PSAP gene's primary role is to produce prosaposin, which subsequently yields saposins A, B, C, and D. These saposins are critical cofactors for lysosomal enzymes that metabolise sphingolipids. Saposin B, for instance, works with enzymes like arylsulphatase A to break down sulphatides, particularly in the myelin-rich white matter of the nervous system, which insulates and protects nerve fibres. This suggests a vital role in neurological health.
Saposin C is essential for the enzyme beta-glucocerebrosidase to break down glucocerebroside, another important sphingolipid. Saposins A and D also contribute to the intricate process of sphingolipid catabolism. By facilitating the enzymatic breakdown of these lipids, the PSAP gene ensures that they do not accumulate to toxic levels within the cell, which could otherwise impair cellular function and lead to disease [PMID:16091807].
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Chromosome location
The PSAP gene is situated on chromosome 10, specifically at position 10q22.1. This genomic location specifies where the gene can be found within the human genome, indicating its precise address on the long arm of chromosome 10.
Protein structure
The prosaposin protein, encoded by the PSAP gene, is composed of 524 amino acids. It features a complex domain architecture that includes multiple saposin domains critical for its function. These domains are: Saposin A-type 1 (amino acids 18-58), Saposin B-type 1 (amino acids 59-142), Saposin B-type 2 (amino acids 194-275), Saposin B-type 3 (amino acids 311-392), Saposin B-type 4 (amino acids 405-486), and Saposin A-type 2 (amino acids 488-524).
Key variants
Variants within the PSAP gene can alter the structure or function of the prosaposin protein. These genetic changes can lead to a deficiency or dysfunction of one or more of the saposin proteins, impacting the ability to break down specific fatty substances in lysosomes. The clinical consequences depend on which saposin is affected and to what extent its function is impaired.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1005+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Combined PSAP deficiency |
c.1076A>C | p.Glu359Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
c.148C>T | p.Gln50Ter | Pathogenic | ★★☆☆ | Combined PSAP deficiency |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Parkinson disease 24, autosomal dominant, susceptibility to |
c.2T>G | p.Met1Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
c.607C>T | p.Gln203Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
c.645C>A | p.Asn215Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Metachromatic leukodystrophy |
c.679_681del | p.Lys227del | Pathogenic/Likely pathogenic | ★★☆☆ | Gaucher disease due to saposin C deficiency |
c.722_723delinsAA | p.Cys241Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
c.889G>T | p.Glu297Ter | Pathogenic | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Mutations in the PSAP gene are associated with inherited conditions primarily affecting the nervous system due to the accumulation of specific lipids. These conditions are classified as lysosomal storage disorders. For example, some individuals with metachromatic leukodystrophy have PSAP variants leading to saposin B deficiency, which prevents the proper breakdown of sulphatides. Other PSAP variants can affect saposin C, resulting in a disorder that resembles a severe form of Gaucher disease, characterised by neurological issues and enlarged liver and spleen.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PSAP variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PSAP gene is included in several UK NHS national genomic testing panels, indicating its clinical relevance for various conditions. It is listed on the DDG2P panel, as well as panels for Early onset or syndromic epilepsy, Foetal anomalies (R21), Inherited white matter disorders, Intellectual disability, Krabbe disease - Saposin A deficiency (R281), Leukodystrophy, adult onset (R62), Likely inborn error of metabolism (R98), Lysosomal storage disorder (R276), Mucopolysaccharideosis, Gaucher, Fabry, Neurodegenerative disorders, adult onset, and Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification - childhood onset.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the PSAP gene?
The PSAP gene provides instructions for making prosaposin, which is then processed into four smaller saposin proteins. These saposins are crucial for helping lysosomal enzymes break down fatty substances called sphingolipids in cells.
What happens if the PSAP gene doesn't function correctly?
If the PSAP gene does not function correctly, it can lead to a deficiency in one or more saposin proteins. This can cause fatty substances (sphingolipids) to accumulate to toxic levels within cells, leading to various lysosomal storage disorders, often affecting the nervous system.
Are there specific conditions associated with PSAP gene variants?
Yes, variants in the PSAP gene have been linked to conditions such as a form of metachromatic leukodystrophy, due to saposin B deficiency, and a disorder resembling severe Gaucher disease, caused by saposin C dysfunction.
References
- Tamargo RJ, Velayati A, Goldin E. The role of saposin C in Gaucher disease. Molecular genetics and metabolism. 2012. PMID: 22652185
- Szymańska K, Ługowska A, Laure-Kamionowska M. Diagnostic difficulties in Krabbe disease: a report of two cases and review of literature. Folia neuropathologica. 2012. PMID: 23319190
- Al-Hassnan ZN, Al Dhalaan H, Patay Z. Sphingolipid activator protein B deficiency: report of 9 Saudi patients and review of the literature. Journal of child neurology. 2009. PMID: 19955343
- Deconinck N, Messaaoui A, Ziereisen F. Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2008. PMID: 17616409
- Grossi S, Regis S, Rosano C. Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. Human mutation. 2008. PMID: 18693274
- Diaz-Font A, Cormand B, Santamaria R. A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity. Human genetics. 2005. PMID: 15856305