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PIGA
phosphatidylinositol glycan anchor biosynthesis class A
The *PIGA* gene provides instructions for synthesising an enzyme crucial for the production of glycophosphatidylinositol (GPI) anchors, which attach many proteins to the cell surface. The *PIGA* gene encodes a protein that initiates the biosynthesis of glycophosphatidylinositol (GPI) anchors.
PIGA is located on the short (p) arm of chromosome X, at band Xp22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The *PIGA* (phosphatidylinositol glycan anchor biosynthesis class A) gene plays a fundamental role in cellular biology by directing the formation of an enzyme involved in the initial steps of glycophosphatidylinositol (GPI) anchor synthesis. GPI anchors are complex glycolipids that serve as a crucial attachment mechanism, linking a variety of proteins to the cell surface.
Disruptions in the *PIGA* gene's function can lead to impaired GPI anchor production, affecting the proper localisation and function of numerous GPI-anchored proteins. This can result in a range of health conditions, including blood disorders and developmental issues.
What the gene does
The *PIGA* gene encodes the PIG-A protein, an enzyme essential for the biosynthesis of glycophosphatidylinositol (GPI) anchors. Specifically, the PIG-A protein is a component of a multi-protein complex that catalyses the first committed step in GPI anchor assembly: the transfer of N-acetylglucosamine (GlcNAc) to phosphatidylinositol (PI) to form GlcNAc-PI. This reaction is fundamental to initiating the entire GPI anchor pathway.
GPI anchors are critical for attaching various proteins to the outer leaflet of the plasma membrane. These GPI-anchored proteins are involved in a wide array of cellular processes, including cell adhesion, signal transduction, complement regulation, and enzymatic activities at the cell surface. Proper GPI anchoring ensures these proteins are correctly positioned to perform their functions, which are vital for normal physiological processes and protecting cells from destruction.
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Chromosome location
The *PIGA* gene is located on the short arm of the X chromosome at position Xp22.2. The PIGA protein consists of 484 amino acids.
Protein structure
The PIGA protein, composed of 484 amino acids, possesses specific regions critical for its function. A notable region spanning amino acids 443-465 is required for its proper localisation to the rough endoplasmic reticulum membrane, where the initial steps of GPI anchor biosynthesis occur. This localisation is essential for the protein to effectively participate in the enzymatic complex responsible for GPI anchor production.
Key variants
Variants within the *PIGA* gene can disrupt its normal function, leading to a reduction or complete absence of functional PIG-A protein. These genetic changes can range from single nucleotide changes to larger deletions or insertions, and their impact varies depending on the specific alteration and its effect on protein production or activity.
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.1234C>T | p.Arg412Ter | Pathogenic | ★★☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.145G>A | p.Val49Met | Pathogenic/Likely pathogenic | ★★☆☆ | Paroxysmal nocturnal hemoglobinuria 1 |
c.355C>T | p.Arg119Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.356G>A | p.Arg119Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.1028del | p.Asn343fs | Pathogenic | ★☆☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.1030_1032del | p.Leu344del | Pathogenic | ★☆☆☆ | not provided |
c.1354G>A | p.Asp452Asn | Pathogenic | ★☆☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.350T>C | p.Phe117Ser | Pathogenic | ★☆☆☆ | Multiple congenital anomalies-hypotonia-seizures syndrome 2 |
c.404C>T | p.Ala135Val | Pathogenic | ★☆☆☆ | not provided |
c.54_55del | p.Arg19fs | Pathogenic | ★☆☆☆ | not provided |
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 *PIGA* gene are associated with several conditions, notably paroxysmal nocturnal haemoglobinuria (PNH). PNH is an acquired clonal disorder characterised by defective GPI anchor synthesis on blood cells, leading to chronic haemolysis and an increased risk of blood clots. Inherited (germline) variants can cause PIGA deficiency, a broader spectrum of conditions with variable severity, typically featuring intellectual disability, seizures (e.g., infantile spasms), hypotonia, and brain abnormalities. The gene is also associated with Simpson-Golabi-Behmel syndrome.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGA variants typically follow X-linked inheritance.
Carrier frequency by population How common is heterozygous PIGA carrier status across ancestry groups?UK clinical status
The *PIGA* gene is included on several UK NHS national genomic testing panels, indicating its clinical significance. It is part of panels for Congenital disorders of glycosylation, DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Thrombophilia with a likely monogenic cause (R97), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PIGA gene?
The *PIGA* gene provides instructions for making an enzyme that initiates the biosynthesis of glycophosphatidylinositol (GPI) anchors. These anchors are crucial for attaching many proteins to the cell surface, enabling various cellular functions.
What conditions are associated with variants in the PIGA gene?
Variants in the *PIGA* gene are primarily associated with paroxysmal nocturnal haemoglobinuria (PNH) and PIGA deficiency. PIGA deficiency encompasses a range of conditions that can include intellectual disability, seizures, and other developmental issues.
How is PIGA gene-related PNH inherited?
Paroxysmal nocturnal haemoglobinuria (PNH) caused by *PIGA* variants is typically an acquired condition, meaning the genetic change occurs in a blood stem cell during a person's lifetime rather than being inherited from parents.
References
- Brodsky RA, Hu R. PIG-A mutations in paroxysmal nocturnal hemoglobinuria and in normal hematopoiesis. Leukemia & lymphoma. 2006. PMID: 16923549
- Mortazavi Y, Merk B, McIntosh J. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Blood. 2003. PMID: 12424196
- Inoue N, Murakami Y, Kinoshita T. Molecular genetics of paroxysmal nocturnal hemoglobinuria. International journal of hematology. 2003. PMID: 12627844
- Rosti V. The molecular basis of paroxysmal nocturnal hemoglobinuria. Haematologica. 2000. PMID: 10629597