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PIGA
phosphatidylinositol glycan anchor biosynthesis class A
The *PIGA* gene provides instructions for a protein critical to the initial steps of glycophosphatidylinositol (GPI) anchor biosynthesis, a process vital for attaching various proteins to cell membranes. The *PIGA* gene encodes a protein involved in the production of GPI anchors, which are crucial for securing many proteins to the cell surface.
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* gene, or phosphatidylinositol glycan anchor biosynthesis class A, plays a fundamental role in human biology by directing the synthesis of an enzyme involved in glycophosphatidylinositol (GPI) anchor formation. GPI anchors are lipid-sugar structures that attach numerous proteins to the outer surface of cell membranes, enabling their diverse functions.
Proteins anchored by GPI perform critical tasks, including cell adhesion, signal transduction, and protecting cells from immune system components. Consequently, impairments in the *PIGA* gene can disrupt these essential cellular processes, leading to a range of health conditions.
What the gene does
The protein encoded by the *PIGA* gene is a key component of a protein complex that initiates the glycophosphatidylinositol (GPI) anchor biosynthesis pathway. Specifically, it facilitates the very first step in this pathway: the creation of an intermediate molecule called N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI). This molecule then undergoes further modifications to become a mature GPI anchor.
The finished GPI anchor is essential for anchoring a variety of proteins, known as GPI-anchored proteins, to the cell membrane. These GPI-anchored proteins are integral to numerous physiological processes. They contribute to cell-to-cell communication, facilitate cell attachment, and help protect cells from certain types of damage, particularly from components of the immune system. Therefore, proper *PIGA* gene function is vital for maintaining cellular integrity and normal physiological responses.
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Chromosome location
The *PIGA* gene is situated on the short (p) arm of the X chromosome, specifically at position Xp22.2. This location indicates its position on the sex chromosome, which is relevant for its X-linked inheritance pattern.
Protein structure
The PIGA protein consists of 484 amino acids. A specific region spanning amino acids 443 to 465 is required for its proper localisation to the rough endoplasmic reticulum membrane, where its enzymatic activity takes place.
Key variants
Genetic changes, often referred to as variants, in the *PIGA* gene can lead to altered protein function or complete loss of function. These variants can affect the protein's ability to participate in GPI anchor biosynthesis, leading to a deficiency of functional GPI anchors on cell surfaces. The resulting impact on cell function can range in severity and presentation.
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.54_55del | p.Arg19fs | Pathogenic | ★☆☆☆ | not provided |
c.68dup | p.Ser24fs | 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
Variants in the *PIGA* gene are associated with several inherited conditions. One notable condition is paroxysmal nocturnal haemoglobinuria (PNH), which typically arises from somatic (acquired) variants in blood stem cells. Inherited (germline) variants can cause PIGA deficiency, a spectrum of conditions with varied features including severe intellectual disability, seizures, weak muscle tone, and developmental abnormalities of the brain and spinal cord. Additionally, variants in *PIGA* are related to 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.
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
The *PIGA* gene is included in several NHS Genomic Medicine Service national test panels. It is listed as green on 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, indicating its clinical significance in these areas within the UK.
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 a protein that performs the first step in creating glycophosphatidylinositol (GPI) anchors. These anchors are crucial for attaching many essential proteins to the surface of cells.
How does the PIGA gene relate to paroxysmal nocturnal haemoglobinuria (PNH)?
Variants in the *PIGA* gene are a known cause of paroxysmal nocturnal haemoglobinuria (PNH). These variants typically occur in blood stem cells and lead to a deficiency of GPI-anchored proteins on blood cell surfaces, causing symptoms like red blood cell breakdown and an increased risk of blood clots.
Is PIGA deficiency an inherited condition?
Yes, inherited (germline) variants in the *PIGA* gene can cause PIGA deficiency. This is a group of conditions with varying severity, often characterised by neurological issues such as intellectual disability and seizures, as well as physical developmental differences.
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