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PSAP
prosaposin
The *PSAP* gene encodes prosaposin, a precursor protein critical for producing smaller saposin proteins that facilitate the breakdown of fatty substances in lysosomes. The *PSAP* gene is responsible for creating prosaposin, which is subsequently processed into four distinct saposin proteins (A, B, C, and D).
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, also known as prosaposin, provides the blueprint for a protein that is fundamental to several biological processes, including the healthy development of the nervous and reproductive systems. The full prosaposin protein is a precursor to smaller, active proteins called saposins, which are vital for cellular waste processing.
After its production, prosaposin is cleaved into four separate saposin proteins: A, B, C, and D. These saposins are primarily found within lysosomes, which are organelles within cells responsible for breaking down and recycling waste materials. Here, saposins aid lysosomal enzymes in the degradation of complex fatty substances known as sphingolipids.
What the gene does
The prosaposin protein, encoded by the *PSAP* gene, plays a critical role in cellular metabolism by facilitating the breakdown of sphingolipids within lysosomes. Once processed, individual saposin proteins assist specific lysosomal enzymes. For instance, saposin B works alongside enzymes like arylsulfatase A to break down sulfatides, which are particularly important in the white matter of the nervous system. Myelin, which insulates nerves, contains these sulfatides.
Saposin C is involved with the enzyme beta-glucocerebrosidase in breaking down glucocerebroside, another type of sphingolipid. Saposins A and D also contribute to the overall process of sphingolipid metabolism. This coordinated action ensures that fatty substances are properly recycled, preventing their toxic accumulation and supporting normal cellular function.
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Chromosome location
The *PSAP* gene is situated on chromosome 10, specifically at position 10q22.1. This genomic location refers to the long (q) arm of chromosome 10, within region 22, band 1.
Protein structure
The prosaposin protein is composed of 524 amino acids and features several distinct domains that become the individual saposin proteins upon cleavage. These include a Saposin A-type 1 domain spanning amino acids 18-58 and a Saposin A-type 2 domain from amino acids 488-524. Additionally, there are four Saposin B-type domains: Saposin B-type 1 (amino acids 59-142), Saposin B-type 2 (amino acids 194-275), Saposin B-type 3 (amino acids 311-392), and Saposin B-type 4 (amino acids 405-486).
Key variants
Variants in the *PSAP* gene can affect the production or function of prosaposin or its derived saposin proteins. These genetic changes can disrupt the normal breakdown of specific fatty substances within lysosomes, leading to their accumulation. The consequences of such accumulation depend on which saposin protein is affected and the extent of its dysfunction.
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 | ★★☆☆ | Sphingolipid activator protein 1 deficiency |
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 | ★★☆☆ | Gaucher disease due to saposin C deficiency |
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
Genetic changes in the *PSAP* gene are associated with inherited conditions primarily affecting the nervous system and other organs due to impaired lipid metabolism. Deficiencies in specific saposin proteins can lead to distinct disorders. For example, a shortage of saposin B can result in a form of metachromatic leukodystrophy, where sulfatides build up to toxic levels in the nervous system. Similarly, issues with saposin C function can resemble a severe form of Gaucher disease, characterised by neurological problems and an 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 panels within the UK's NHS Genomic Medicine Service via PanelApp. It is listed for conditions such as early onset or syndromic epilepsy, foetal anomalies (R21), inherited white matter disorders, intellectual disability, and specific lysosomal storage disorders like Krabbe disease (Saposin A deficiency, R281). It is also relevant to the investigation of adult-onset leukodystrophy (R62), likely inborn errors of metabolism (R98), and other neurodegenerative and undiagnosed metabolic disorders.
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 within cells.
What happens if there is a problem with the PSAP gene?
Problems with the *PSAP* gene can lead to a deficiency in one or more saposin proteins. This can impair the breakdown of specific fatty substances, causing them to accumulate to toxic levels and result in inherited conditions affecting the nervous system and other organs, such as forms of metachromatic leukodystrophy or Gaucher disease-like symptoms.
How does the PSAP gene relate to neurological health?
The *PSAP* gene is vital for neurological health because its derived saposin proteins, particularly saposin B, assist in breaking down sulfatides that are abundant in the myelin sheath protecting nerve fibres. Dysfunction can lead to the accumulation of these lipids, negatively impacting nerve function and contributing to neurodegenerative conditions.
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