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G6PD
glucose-6-phosphate dehydrogenase
The G6PD gene provides instructions for producing the enzyme glucose-6-phosphate dehydrogenase, which is crucial for protecting red blood cells from oxidative damage. The G6PD gene is essential for proper carbohydrate processing and safeguards red blood cells against damage and premature destruction.
G6PD is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The G6PD gene encodes the enzyme glucose-6-phosphate dehydrogenase, which plays a vital role in cellular metabolism, particularly within red blood cells. This enzyme is involved in the pentose phosphate pathway, a crucial biochemical route for maintaining cellular health.
Its primary function is to help protect cells from oxidative stress. Dysfunction of the G6PD enzyme is linked to several inherited conditions.
What the gene does
The glucose-6-phosphate dehydrogenase enzyme, produced from the G6PD gene, is integral to the first step of the pentose phosphate pathway. This metabolic pathway converts glucose into ribose-5-phosphate, a precursor for nucleotides which are the building blocks of DNA and RNA.
A key product of this reaction is NADPH (nicotinamide adenine dinucleotide phosphate). NADPH is critical for protecting cells against reactive oxygen species, which are potentially harmful byproducts of normal cellular processes. By generating NADPH, the enzyme helps prevent these harmful molecules from accumulating to toxic levels within cells. This protective mechanism is especially important in red blood cells, which are highly susceptible to oxidative damage and rely almost exclusively on G6PD for NADPH production, as they lack alternative NADPH-generating enzymes.
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Chromosome location
The G6PD gene is situated on the X chromosome at position Xq28. This chromosomal location means that conditions associated with G6PD gene variants typically follow an X-linked inheritance pattern.
Protein structure
The G6PD protein is composed of 515 amino acids, which assemble to form the functional enzyme with distinct catalytic domains necessary for its metabolic activity.
Key variants
Over 200 distinct genetic variants associated with G6PD deficiency have been identified within the G6PD gene. These variants predominantly involve alterations to single amino acids, which can affect the enzyme's structure, impair its function, or reduce the overall amount of enzyme produced within cells. These changes can significantly impact the enzyme's protective role.
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.1139T>C | p.Ile380Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.1246G>A | p.Glu416Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.130G>A | p.Ala44Thr | Pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.241C>T | p.Arg81Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.463C>G | p.His155Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.496C>T | p.Arg166Cys | Pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.497G>A | p.Arg166His | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.519C>G | p.Phe173Leu | Pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.595A>G | p.Ile199Val | Pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD deficiency |
c.679C>T | p.Arg227Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Anemia, nonspherocytic hemolytic, due to G6PD 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
Variants in the G6PD gene are primarily associated with conditions such as G6PD deficiency and hereditary haemolytic anaemia. These conditions result from the enzyme's inability to adequately protect red blood cells from oxidative stress, leading to their premature destruction.
- G6PD deficiency
- Hereditary haemolytic anaemia (G6PD) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic G6PD variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
In the UK, the G6PD gene is part of several NHS Genomic Medicine Service clinical panels. It is included in panels for COVID-19 research, cytopenias and congenital anaemias, primary immunodeficiency or monogenic inflammatory bowel disease, and rare anaemia, reflecting its importance in diagnostic screening within these areas.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the G6PD enzyme?
The G6PD enzyme's main role is to produce NADPH, a molecule vital for protecting cells, especially red blood cells, from damage caused by reactive oxygen species.
How do G6PD gene variants affect the enzyme?
G6PD gene variants typically alter the enzyme's structure or reduce its production, impairing its ability to protect cells from oxidative stress and leading to conditions like G6PD deficiency.
Is G6PD deficiency an inherited condition?
Yes, G6PD deficiency is an inherited condition. It typically follows an X-linked inheritance pattern because the G6PD gene is located on the X chromosome.
References
- Luzzatto L, Nannelli C, Notaro R. Glucose-6-Phosphate Dehydrogenase Deficiency. Hematology/oncology clinics of North America. 2016. PMID: 27040960
- Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet (London, England). 2008. PMID: 18177777
- Efferth T, Schwarzl SM, Smith J. Role of glucose-6-phosphate dehydrogenase for oxidative stress and apoptosis. Cell death and differentiation. 2006. PMID: 16311511
- Verrelli BC, McDonald JH, Argyropoulos G. Evidence for balancing selection from nucleotide sequence analyses of human G6PD. American journal of human genetics. 2002. PMID: 12378426