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GSS
glutathione synthetase
The GSS gene provides instructions for synthesising glutathione synthetase, an enzyme critical for producing glutathione, a key cellular antioxidant. The GSS gene encodes the enzyme glutathione synthetase, which is vital for the final step in synthesising glutathione.
GSS is located on the long (q) arm of chromosome 20, at band 20q11.22. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The GSS gene contains instructions for making an enzyme known as glutathione synthetase. This enzyme plays an essential role in a cellular process called the gamma-glutamyl cycle. This cycle is a series of chemical reactions necessary for the production of glutathione, a small molecule crucial for maintaining cellular health.
Glutathione acts as an antioxidant, safeguarding cells from harm caused by unstable oxygen-containing molecules. These reactive molecules are natural byproducts of the body's energy production. Additionally, glutathione is involved in processing medications, neutralising harmful compounds, and supporting the synthesis of DNA, proteins, and other vital cellular components.
What the gene does
The GSS gene directs the synthesis of glutathione synthetase, an enzyme that catalyses the final step in glutathione production. Glutathione is a tripeptide molecule composed of three amino acids. This synthesis occurs within the gamma-glutamyl cycle, a sequence of biochemical reactions prevalent in most cell types throughout the body.
Glutathione's primary function is its antioxidant activity, which involves protecting cells against oxidative stress. Oxidative stress arises from unstable oxygen-containing molecules generated during normal metabolic processes. By neutralising these molecules, glutathione helps prevent cellular damage. Beyond its antioxidant role, glutathione also contributes to the detoxification of various substances, including certain medications and carcinogens, and is important for the synthesis of key biomolecules such as DNA and proteins.
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Chromosome location
The GSS gene is situated on chromosome 20, specifically at position 20q11.22. This chromosomal location indicates its precise address within the human genome. The gene encodes a protein consisting of 474 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the GSS gene can lead to changes in the glutathione synthetase enzyme, potentially affecting its function. These changes range from single nucleotide alterations to larger structural variations. Pathogenic variants can impair the enzyme's ability to produce glutathione effectively.
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.1139_1144del | p.Val380_Gln381del | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency without 5-oxoprolinuria |
c.1227C>A | p.Cys409Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency with 5-oxoprolinuria |
c.1252C>T | p.Arg418Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency without 5-oxoprolinuria |
c.127G>T | p.Glu43Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency without 5-oxoprolinuria |
c.129+1663A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | GSS-related disorders |
c.130-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency with 5-oxoprolinuria |
c.490C>T | p.Arg164Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency with 5-oxoprolinuria |
c.574del | p.Ile192fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency without 5-oxoprolinuria |
c.588G>A | p.Trp196Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive GSS-related disorders |
c.656A>C | p.Asp219Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Glutathione synthetase deficiency without 5-oxoprolinuria |
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 GSS gene are associated with glutathione synthetase deficiency. This condition is characterised by a range of symptoms, including haemolytic anaemia (abnormal destruction of red blood cells), 5-oxoprolinuria (high levels of 5-oxoproline in the urine), and metabolic acidosis (increased acidity in the blood and tissues). More than 30 different mutations have been identified in individuals with this condition.
No disease links recorded for this gene in our reference set.
UK clinical status
The GSS gene is included in several NHS England Genomic Medicine Service approved panels. It is part of the 'Cytopenias and congenital anaemias', 'Likely inborn error of metabolism' (R98), 'Rare anaemia' (R92), and 'Undiagnosed metabolic disorders' panels. This indicates its clinical relevance in diagnosing a range of inherited conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the GSS gene do?
The GSS gene provides instructions for making the enzyme glutathione synthetase, which is responsible for synthesising glutathione. Glutathione is a crucial antioxidant that protects cells from damage and aids in detoxification processes.
What is glutathione synthetase deficiency?
Glutathione synthetase deficiency is a condition caused by mutations in the GSS gene. It leads to impaired glutathione production and can manifest with symptoms like haemolytic anaemia, 5-oxoprolinuria, and metabolic acidosis.
Where is the GSS gene located?
The GSS gene is located on chromosome 20 at position 20q11.22. This is its specific address within the human genetic code.
References
- De Jesus MC, Ingle BL, Barakat KA. The role of strong electrostatic interactions at the dimer interface of human glutathione synthetase. The protein journal. 2014. PMID: 25070563
- Dinescu A, Brown TR, Barelier S. The role of the glycine triad in human glutathione synthetase. Biochemical and biophysical research communications. 2010. PMID: 20800579
- Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet journal of rare diseases. 2007. PMID: 17397529
- Dinescu A, Cundari TR, Bhansali VS. Function of conserved residues of human glutathione synthetase: implications for the ATP-grasp enzymes. The Journal of biological chemistry. 2004. PMID: 14990577
- Njålsson R, Carlsson K, Bhansali V. Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes. The Biochemical journal. 2004. PMID: 15056072
- Njålsson R, Carlsson K, Olin B. Kinetic properties of missense mutations in patients with glutathione synthetase deficiency. The Biochemical journal. 2000. PMID: 10861239
- Janáky R, Ogita K, Pasqualotto BA. Glutathione and signal transduction in the mammalian CNS. Journal of neurochemistry. 1999. PMID: 10461878