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PIGO
phosphatidylinositol glycan anchor biosynthesis class O
The PIGO gene provides instructions for a component of an enzyme crucial for synthesising glycosylphosphatidylinositol (GPI) anchors, which are vital for attaching certain proteins to cell surfaces. PIGO is a gene that plays an essential role in the production of glycosylphosphatidylinositol (GPI) anchors.
PIGO is located on the short (p) arm of chromosome 9, at band 9p13.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 9 in the library →Overview
The PIGO gene, formally known as phosphatidylinositol glycan anchor biosynthesis class O, is involved in a critical cellular process: the formation of glycosylphosphatidylinositol (GPI) anchors. These anchors are essential for attaching specific proteins to the cell surface, allowing them to interact with their environment and carry out vital biological functions. The PIGO gene provides the genetic blueprint for one part of an enzyme called GPI ethanolamine phosphate transfer 3 (GPI-ET3).
What the gene does
The protein encoded by the PIGO gene is a subunit of the GPI-ET3 enzyme, which is fundamental to the biosynthesis pathway of GPI anchors. Specifically, the GPI-ET3 enzyme facilitates the addition of an ethanolamine phosphate molecule to the nascent GPI anchor structure within the endoplasmic reticulum. This step is crucial because the added ethanolamine phosphate group is required for the subsequent attachment of the completed GPI anchor to various proteins. Once bound to a protein, the GPI anchor then directs the protein to the outer surface of the cell membrane, ensuring its proper localisation and function. The PIGO protein works in conjunction with a protein encoded by the PIGF gene to form the complete and functional GPI-ET3 enzyme.
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Chromosome location
The PIGO gene is situated on the short arm of chromosome 9, at position 13.3 (9p13.3). This chromosomal location specifies where the gene is found within the human genome.
Protein structure
The PIGO gene codes for a protein that is 1089 amino acids long. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the PIGO gene can lead to alterations in the protein's structure and function, potentially impairing the proper biosynthesis of GPI anchors. These genetic changes can range from single amino acid substitutions to larger deletions or insertions, and their impact depends on the specific nature and location of the variant within the gene. Such variants are typically inherited in an autosomal recessive manner.
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.3069+5G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.1114C>T | p.Gln372Ter | Pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.1126C>T | p.Arg376Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.1271_1272del | p.Val424fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.1549del | p.Ala517fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.1810dup | p.Arg604fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.2191del | p.Arg731fs | Pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.2191dup | p.Arg731fs | Pathogenic/Likely pathogenic | ★★☆☆ | PIGO-related disorder |
c.2361dup | p.Thr788fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
c.2404C>T | p.Arg802Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 2 |
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 PIGO gene are known to cause Mabry syndrome, an inherited condition characterised by intellectual disability, distinct facial features, and elevated levels of alkaline phosphatase in the blood (hyperphosphatasia). The disruption to GPI anchor biosynthesis due to PIGO variants underlies the varied symptoms observed in affected individuals.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGO 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
PIGO is recognised within the NHS Genomic Medicine Service due to its clinical relevance. It is listed on several Green panels in PanelApp UK, indicating that there is strong evidence for its association with human disease. These include panels for Congenital disorders of glycosylation, DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is a GPI anchor and why is it important?
A GPI anchor is a special type of molecule that attaches certain proteins to the outside of a cell's membrane. This attachment is crucial for these proteins to perform their various roles, such as cell signalling and enzymatic functions, by correctly positioning them on the cell surface.
How does the PIGO gene contribute to GPI anchor formation?
The PIGO gene provides instructions for one part of the GPI ethanolamine phosphate transfer 3 (GPI-ET3) enzyme. This enzyme adds an ethanolamine phosphate molecule to the developing GPI anchor, which is a necessary step for the anchor to later attach to specific proteins within the cell.
What is Mabry syndrome?
Mabry syndrome is a genetic condition caused by pathogenic variants in the PIGO gene. It is characterised by intellectual disability, distinctive facial features, and abnormally high levels of alkaline phosphatase in the blood, resulting from impaired GPI anchor formation.
References
- Krawitz PM, Murakami Y, Hecht J. Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. American journal of human genetics. 2012. PMID: 22683086
- Tsai YH, Liu X, Seeberger PH. Chemical biology of glycosylphosphatidylinositol anchors. Angewandte Chemie (International ed. in English). 2012. PMID: 23086912
- Hong Y, Maeda Y, Watanabe R. Requirement of PIG-F and PIG-O for transferring phosphoethanolamine to the third mannose in glycosylphosphatidylinositol. The Journal of biological chemistry. 2000. PMID: 10781593