On this page
PHGDH
phosphoglycerate dehydrogenase
The PHGDH gene provides instructions for phosphoglycerate dehydrogenase, an enzyme vital for synthesising the amino acid serine, which is critical for central nervous system development and function. The PHGDH gene is responsible for producing the phosphoglycerate dehydrogenase enzyme.
PHGDH is located on the short (p) arm of chromosome 1, at band 1p12. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The PHGDH gene encodes the enzyme phosphoglycerate dehydrogenase. This enzyme is crucial for the synthesis of serine, an amino acid that plays a vital role in numerous biological processes, particularly within the central nervous system [PMID:17900947].
The brain and spinal cord depend on serine for their maturation and ongoing activity. It serves as a component of neurotransmitters, which facilitate signal transmission, and contributes to proteins found in cell membranes and the myelin sheath that insulates nerves [PMID:17900947].
What the gene does
The phosphoglycerate dehydrogenase enzyme, encoded by the PHGDH gene, is composed of four subunits. Its primary function is the first committed step in the de novo synthesis of serine [PMID:17900947]. Specifically, the enzyme converts 3-phosphoglycerate into 3-phosphohydroxypyruvate.
While serine can be acquired through diet, the blood-brain barrier prevents serine obtained from food from entering neural tissue, necessitating local synthesis within the central nervous system. Therefore, the PHGDH enzyme's activity is especially important for maintaining adequate serine levels within the brain, supporting its complex functions and structural integrity.
Video: Genetics 101
Chromosome location
The PHGDH gene is located on chromosome 1 at position 1p12. This region specifies the exact genomic address of the gene within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variations within the PHGDH gene can impact the structure and function of the phosphoglycerate dehydrogenase enzyme. These genetic changes can lead to altered enzyme activity, potentially affecting serine production and subsequent neurological processes.
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.94_110del | p.Glu32fs | 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
Pathogenic variants in the PHGDH gene are associated with phosphoglycerate dehydrogenase deficiency. This condition is characterised by a spectrum of neurological symptoms, which typically include profound neurodevelopmental impairment, a smaller-than-expected head circumference, and seizures that respond poorly to standard anticonvulsant therapy.
No disease links recorded for this gene in our reference set.
UK clinical status
The PHGDH gene is recognised in the UK's NHS Genomic Medicine Service. It is listed on several green-rated PanelApp 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 clinical association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the PHGDH gene?
The PHGDH gene provides instructions for creating the phosphoglycerate dehydrogenase enzyme, which is essential for the body's production of the amino acid serine. Serine is particularly important for the development and function of the brain and spinal cord.
Why is serine important for the brain?
Serine is crucial for brain development and function because it is a component of neurotransmitters that transmit signals in the nervous system. It also forms part of proteins in cell membranes and the myelin sheath, which insulates nerve cells. Neurons synthesise serine internally, as the molecule acquired through diet cannot penetrate the protective vascular barrier surrounding the brain.
What condition is associated with PHGDH gene variants?
Variants in the PHGDH gene can cause phosphoglycerate dehydrogenase deficiency. This condition typically presents with neurological symptoms such as an unusually small head size (microcephaly), severe developmental delay, and difficult-to-treat seizures.
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