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PHGDH
phosphoglycerate dehydrogenase
The PHGDH gene provides instructions for phosphoglycerate dehydrogenase, an enzyme vital for the production of the amino acid serine, particularly in the brain. The PHGDH gene is responsible for encoding an enzyme that plays a critical role in the synthesis of serine, an amino acid essential for central nervous system development and function.
PHGDH is located on the short (p) arm of chromosome 1, at band 1p12. Arm ratio per GRCh38 - banding schematic.
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Overview
The PHGDH gene provides the genetic blueprint for an enzyme called phosphoglycerate dehydrogenase. This enzyme is crucial for the synthesis of serine, a non-essential amino acid that is vital for various bodily functions. Serine is particularly important for the development and proper functioning of the brain and spinal cord, collectively known as the central nervous system.
What the gene does
The phosphoglycerate dehydrogenase enzyme, encoded by the PHGDH gene, is composed of four identical subunits. This enzyme initiates the synthesis pathway for the amino acid serine by converting 3-phosphoglycerate into 3-phosphohydroxypyruvate. Serine is a fundamental building block for proteins and is involved in forming neurotransmitters, which are chemical messengers in the nervous system. Additionally, serine is a component of cell membrane proteins and the myelin sheath, a fatty insulating layer around many nerves.
While serine can be obtained through diet, brain cells must produce their own supply. This is because dietary serine cannot readily cross the blood-brain barrier, a protective mechanism that regulates substance passage between blood vessels and the brain. Therefore, the PHGDH enzyme's function in brain serine synthesis is indispensable for neurological health.
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Chromosome location
The PHGDH gene is located on the short arm of chromosome 1, at position 1p12. This specific genomic address helps in identifying and studying the gene within the human genome.
Protein structure
The phosphoglycerate dehydrogenase protein consists of 533 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the PHGDH gene can alter the function of the phosphoglycerate dehydrogenase enzyme. These changes can range from single amino acid substitutions to more significant alterations, potentially impacting the enzyme's ability to synthesise serine 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.1394del | p.Leu465fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neu-Laxova syndrome 1 |
c.1518G>A | p.Trp506Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.1A>C | p.Met1Leu | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.211C>T | p.Gln71Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.367C>T | p.Gln123Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.399G>A | p.Trp133Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.476_477del | p.Glu159fs | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.665_666dup | p.Ala223fs | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.889G>T | p.Glu297Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH deficiency |
c.992del | p.Pro331fs | Pathogenic/Likely pathogenic | ★★☆☆ | PHGDH 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 PHGDH gene are primarily associated with phosphoglycerate dehydrogenase deficiency. This condition is characterised by a constellation of neurological symptoms resulting from impaired serine synthesis. The severity and specific manifestations can vary among affected individuals.
No disease links recorded for this gene in our reference set.
UK clinical status
The PHGDH gene is recognised within the NHS Genomic Medicine Service. It is listed as 'green' on several NHS England National Genomic Test Directory panels, including DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Foetal hydrops, Intellectual disability, Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This indicates that variants in PHGDH are considered to have a strong association with these conditions in a clinical diagnostic context.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PHGDH gene?
The PHGDH gene provides instructions for making the phosphoglycerate dehydrogenase enzyme, which is essential for the body's production of the amino acid serine. Serine is crucial for the development and function of the central nervous system, particularly in the brain.
What is phosphoglycerate dehydrogenase deficiency?
Phosphoglycerate dehydrogenase deficiency is a condition caused by changes in the PHGDH gene. It is characterised by symptoms such as an unusually small head size (microcephaly), severe developmental delays, and seizures that are difficult to treat.
Why is serine production in the brain so important?
Serine is vital for brain development and function because it is a component of neurotransmitters and structural elements like cell membranes and myelin. Brain cells must produce their own serine as dietary serine cannot easily cross the blood-brain barrier, making the PHGDH enzyme's role in brain serine synthesis critical.
References
- Tabatabaie L, de Koning TJ, Geboers AJ. Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Human mutation. 2009. PMID: 19235232
- Fuchs SA, Dorland L, de Sain-van der Velden MG. D-serine in the developing human central nervous system. Annals of neurology. 2006. PMID: 17068790
- de Koning TJ, Klomp LW. Serine-deficiency syndromes. Current opinion in neurology. 2004. PMID: 15021249