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PIGQ
phosphatidylinositol glycan anchor biosynthesis class Q
PIGQ encodes a protein required for attaching GPI anchors to proteins destined for cell membranes, a process critical for nervous system development and function. The PIGQ gene provides instructions for making a component of the GPI transamidase complex, which adds glycosylphosphatidylinositol (GPI) anchors to proteins destined for the cell membrane.
PIGQ is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q, a subunit of the GPI transamidase complex. This molecular machinery attaches GPI anchors to newly synthesised proteins, enabling them to embed in the cell membrane. GPI-anchored proteins participate in diverse cellular processes including cell signalling, immune responses, and neuronal development.
Pathogenic variants in PIGQ follow an autosomal recessive inheritance pattern, meaning two altered copies are needed to cause clinical features. The gene is recognised on multiple NHS Genomic Medicine Service gene panels for neurogenetics, reflecting its importance in conditions affecting brain function and development.
What the gene does
The PIGQ protein functions as a catalytic component of the GPI transamidase complex, a multi-subunit enzyme that operates in the endoplasmic reticulum. This complex cleaves a signal peptide from nascent proteins and simultaneously links a pre-assembled GPI anchor to the newly exposed C-terminal amino acid. The attachment process is essential for hundreds of proteins that require membrane localisation without transmembrane domains.
GPI-anchored proteins perform varied roles at the cell surface. In the nervous system, these proteins contribute to synapse formation, axon guidance, and neuronal signalling. The transamidase complex must function precisely to maintain appropriate protein trafficking and membrane composition. PIGQ specifically participates in the substrate recognition and catalytic steps of anchor transfer, working alongside other subunits including PIGK, PIGT, PIGU, and GPAA1 to coordinate this multi-step reaction.
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Chromosome location
PIGQ is located on chromosome 16 at position 16p13.3 on the short arm. This chromosomal territory contains numerous genes and is susceptible to structural rearrangements. The gene spans multiple exons that encode a 447-amino-acid protein product.
Protein structure
The PIGQ protein comprises 447 amino acids. PIGQ contains multiple transmembrane domains that enable its integration into the ER membrane and participation in the GPI transamidase complex. While complete high-resolution crystal structure data are not yet available, biochemical studies have identified key functional regions required for substrate recognition and catalysis.
Key variants
Pathogenic variants in PIGQ typically cause loss of protein function, impairing GPI anchor attachment. Most disease-causing changes are missense variants that disrupt the protein's structure or its interactions within the transamidase complex, though nonsense and frameshift variants have also been reported. The severity of neurological features may correlate with residual enzyme activity, as complete loss of GPI anchor biosynthesis is thought to be incompatible with life based on model organism studies.
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.1199_1201del | p.Tyr400del | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 77 |
c.241del | p.Leu81fs | Pathogenic/Likely pathogenic | ★★☆☆ | Epilepsy |
c.418C>T | p.Gln140Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy |
c.49G>A | p.Gly17Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 77 |
c.811C>T | p.Gln271Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epilepsy |
c.942+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.942+1G>C | - | Pathogenic | ★★☆☆ | Epilepsy |
c.968_969del | p.Leu323fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
g.(?_578765)_(579200_?)del | - | Pathogenic | ★☆☆☆ | Epilepsy |
c.1024C>T | p.Gln342Ter | Pathogenic | ★☆☆☆ | Epilepsy |
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
Biallelic pathogenic variants in PIGQ are associated with neurological phenotypes that generally include intellectual disability and epilepsy. Affected individuals may present with developmental delay in early childhood, followed by seizures that can be difficult to control. The spectrum of severity varies, with some individuals experiencing additional features such as movement disorders or behavioural challenges. These manifestations reflect the critical role of GPI-anchored proteins in establishing and maintaining neural circuits.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGQ 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
PIGQ appears on several NHS Genomic Medicine Service gene panels with green (high evidence) classification. These include the Early Onset or Syndromic Epilepsy panel (R59), the Intellectual Disability panel (R29), and the Paediatric Disorders additional genes list. Green classification indicates robust evidence supporting the gene-disease relationship, enabling PIGQ testing through NHS genomic laboratories when clinical features align with these panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does PIGQ follow?
PIGQ-related conditions follow autosomal recessive inheritance. An individual must inherit two altered copies of the gene, one from each parent, to develop clinical features. Carriers with one pathogenic variant typically do not show symptoms.
How do PIGQ variants affect protein function?
PIGQ variants typically impair the GPI transamidase complex's ability to attach GPI anchors to proteins. This disrupts the localisation of numerous cell-surface proteins, particularly affecting processes critical for nervous system development and function.
Why is PIGQ included on epilepsy gene panels?
PIGQ variants are recognised as a cause of early-onset or syndromic epilepsy, often accompanied by intellectual disability. The gene's inclusion on NHS epilepsy panels reflects consistent evidence linking PIGQ dysfunction to seizure disorders in affected individuals.