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PIGV
phosphatidylinositol glycan anchor biosynthesis class V
The PIGV gene provides instructions for making an enzyme crucial in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, which are vital for attaching certain proteins to the cell surface. PIGV encodes the GPI mannosyltransferase 2 enzyme, a key component in the production of GPI anchors.
PIGV is located on the short (p) arm of chromosome 1, at band 1p36.11. Arm ratio per GRCh38 - banding schematic.
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The PIGV gene, also known as phosphatidylinositol glycan anchor biosynthesis class V, plays a fundamental role in cellular biology by encoding an enzyme involved in the creation of glycosylphosphatidylinositol (GPI) anchors. These anchors are complex sugar-lipid structures that serve as an attachment mechanism for numerous proteins to the outer surface of cell membranes. This process is critical for the correct localisation and function of many proteins, impacting a wide range of cellular activities.
Disruptions in the PIGV gene's function can lead to impaired GPI anchor biosynthesis, which in turn affects the proper display of GPI-anchored proteins on the cell surface. Such impairments are associated with a spectrum of health conditions, most notably Mabry syndrome. Understanding the PIGV gene and its associated pathways is important for diagnosing and potentially managing these inherited disorders, highlighting its relevance in neurogenetics and broader genetic studies.
What the gene does
The PIGV gene directs the synthesis of an enzyme called GPI mannosyltransferase 2. This enzyme is an integral part of the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway, which is a complex series of biochemical reactions occurring primarily within the endoplasmic reticulum (ER).
Specifically, GPI mannosyltransferase 2 is responsible for adding the second of three mannose sugar units to the nascent GPI anchor precursor. This mannose transfer step is critical for the correct assembly and maturation of the GPI anchor. Once fully assembled, the GPI anchor binds to specific proteins within the ER. This attachment is a post-translational modification that ensures these proteins can be properly transported and anchored to the outer leaflet of the cell membrane. The accurate display of GPI-anchored proteins on the cell surface is essential for various cellular functions, including cell adhesion, cell signalling, immune responses, and enzyme activity.
Any defect in the PIGV enzyme's activity can lead to a deficiency in functional GPI anchors, resulting in the improper localisation or absence of numerous critical proteins on the cell surface. This disruption in protein display can have widespread effects across different tissues and organs, contributing to the diverse clinical manifestations observed in associated conditions.
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Chromosome location
The PIGV gene is situated on chromosome 1, specifically located at position 1p36.11. This genomic address indicates its precise place within the human genome. Genes found in this region are part of the short arm ('p') of chromosome 1, within band 36, sub-band 11. The PIGV gene encodes a protein that consists of 493 amino acids. Its location makes it part of a region that has been linked to various genetic conditions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the PIGV gene refer to changes in its DNA sequence that can alter the production or function of the GPI mannosyltransferase 2 enzyme. These genetic alterations can range from single nucleotide changes (point variants) to larger deletions or insertions within the gene sequence. Since PIGV plays a crucial role in GPI anchor biosynthesis, variants that impair the enzyme's activity can lead to a deficiency in functional GPI anchors.
Inheritance of pathogenic variants in PIGV typically follows an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop a PIGV-related condition. Individuals who inherit only one altered copy are generally carriers and do not display symptoms. The specific impact of a variant depends on its nature and location within the gene, potentially leading to a spectrum of clinical severity in affected individuals.
Sample of pathogenic variants
9 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.1022C>A | p.Ala341Glu | Pathogenic/Likely pathogenic | ★★☆☆ | PIGV-related disorder |
c.467G>A | p.Cys156Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | PIGV-related disorder |
c.607C>T | p.Arg203Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperphosphatasia with intellectual disability syndrome 1 |
c.1022C>T | p.Ala341Val | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 1 |
c.1154A>C | p.His385Pro | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 1 |
c.766C>A | p.Gln256Lys | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 1 |
c.1253C>A | p.Ala418Asp | Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.55C>T | p.Arg19Cys | Likely pathogenic | ★☆☆☆ | Hyperphosphatasia with intellectual disability syndrome 1 |
c.781dup | p.Thr261fs | Likely 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 PIGV gene are primarily associated with Mabry syndrome. This condition is characterised by intellectual disability, distinctive facial features, and elevated levels of an enzyme called alkaline phosphatase in the blood, known as hyperphosphatasia. Other symptoms may also be present, contributing to the syndrome's broad clinical picture. The genetic basis of Mabry syndrome involves specific changes in the PIGV gene that affect the GPI mannosyltransferase 2 enzyme, thereby disrupting the critical process of GPI anchor biosynthesis.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGV 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
In the UK, the PIGV gene is recognised on several NHS Genomic Medicine Service (GMS) approved panels, indicating its importance in diagnosing specific inherited conditions. It is included on panels such as Clefting, Congenital disorders of glycosylation, DDG2P, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This widespread inclusion underscores the gene's relevance across various clinical presentations and its role in UK diagnostic pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Currently, there is limited specific research regarding direct lifestyle interventions for individuals with PIGV-related conditions. However, a healthy and balanced lifestyle generally supports overall well-being. For individuals with developmental differences associated with conditions like Mabry syndrome, early intervention therapies, educational support, and tailored care plans are often recommended to maximise potential and improve quality of life. Maintaining a supportive home environment and engaging in activities that promote cognitive and physical development may be beneficial. Any lifestyle modifications should always be discussed with a healthcare professional.
Supplement considerations
There is no conclusive evidence that specific dietary supplements can prevent or treat conditions associated with PIGV gene variants. While some individuals may explore various supplements, it is crucial to understand that their efficacy for genetic conditions like Mabry syndrome has not been scientifically established. Individuals considering any supplements should consult with a healthcare professional, as some supplements can interact with medications or have adverse effects, particularly in those with underlying health conditions. A balanced diet generally provides essential nutrients, and supplements should not be seen as a substitute for professional medical advice or treatment.
Frequently asked questions
What is the primary function of the PIGV gene?
The PIGV gene provides instructions for making the GPI mannosyltransferase 2 enzyme, which is essential for adding a specific sugar molecule (mannose) during the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. These anchors are critical for attaching certain proteins to the cell surface.
What condition is associated with variants in the PIGV gene?
Variants in the PIGV gene are primarily associated with Mabry syndrome, a genetic disorder characterised by intellectual disability, distinctive facial features, and hyperphosphatasia (increased levels of alkaline phosphatase in the blood).
How is Mabry syndrome inherited?
Mabry syndrome typically follows an autosomal recessive inheritance pattern. This means an individual must inherit two copies of a pathogenic PIGV variant, one from each parent, to develop the condition.
Is the PIGV gene included on any NHS genetic testing panels?
Yes, the PIGV gene is included on several NHS Genomic Medicine Service (GMS) panels, such as those for Clefting, Congenital disorders of glycosylation, Intellectual disability, and Foetal anomalies, highlighting its diagnostic importance in the UK.
Can lifestyle changes or supplements treat PIGV-related conditions?
There is no conclusive scientific evidence that specific lifestyle changes or dietary supplements can prevent or treat PIGV-related conditions. Any potential interventions should be discussed with a healthcare professional.
References
- Murakami Y, Kanzawa N, Saito K. Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. The Journal of biological chemistry. 2012. PMID: 22228761
- Thompson MD, Roscioli T, Marcelis C. Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome). American journal of medical genetics. Part A. 2012. PMID: 22315194
- Horn D, Krawitz P, Mannhardt A. Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expanded clinical spectrum. American journal of medical genetics. Part A. 2011. PMID: 21739589
- Krawitz PM, Schweiger MR, Rödelsperger C. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nature genetics. 2010. PMID: 20802478