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PIGM
phosphatidylinositol glycan anchor biosynthesis class M
PIGM encodes an enzyme that catalyses a critical step in the biosynthesis of glycosylphosphatidylinositol anchors, molecular tethers that attach proteins to cell membranes. The PIGM gene provides instructions for producing an enzyme involved in building glycosylphosphatidylinositol (GPI) anchors, complex glycolipid structures that link many proteins to the outer surface of cells.
PIGM is located on the long (q) arm of chromosome 1, at band 1q23.2. Arm ratio per GRCh38 - banding schematic.
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The PIGM gene encodes phosphatidylinositol glycan anchor biosynthesis class M, an enzyme that participates in the stepwise assembly of glycosylphosphatidylinositol (GPI) anchors. These anchors serve as membrane attachment points for over 150 different proteins in human cells, enabling them to localise correctly on the cell surface where they perform diverse roles in cell signalling, immune recognition, and tissue development.
Pathogenic variants in PIGM impair GPI anchor production, resulting in congenital disorders of glycosylation characterised by neurological impairment, developmental delay, and seizures. The gene is inherited in an autosomal recessive pattern, meaning affected individuals typically carry two altered copies. PIGM-related conditions are rare but represent an important subset of inherited metabolic disorders affecting glycosylation pathways.
What the gene does
The PIGM enzyme catalyses the first mannosylation step in GPI anchor biosynthesis, transferring a mannose sugar residue onto an early precursor molecule in the endoplasmic reticulum. This reaction is essential for constructing the mature GPI anchor, a glycolipid structure comprising a phosphatidylinositol lipid tail, a glycan core, and a phosphoethanolamine linker that ultimately attaches to proteins.
GPI-anchored proteins include enzymes involved in breaking down extracellular molecules, receptors that mediate cell adhesion, and proteins that regulate complement activation on cell surfaces. Without functional PIGM, cells cannot efficiently produce these anchors, leading to reduced surface expression of GPI-anchored proteins. This deficiency particularly affects tissues with high metabolic demands and complex developmental programmes, such as the developing nervous system.
The PIGM protein functions as part of a multi-subunit mannosyltransferase complex in the endoplasmic reticulum membrane. It works in concert with other enzymes in the GPI biosynthesis pathway to ensure proper assembly and transfer of the anchor to nascent proteins destined for the cell surface.
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Chromosome location
PIGM is located on chromosome 1 at band 1q23.2, a region on the long arm of chromosome 1. The gene spans a relatively compact genomic region and encodes a protein of 423 amino acids. This chromosomal location places PIGM among a cluster of genes involved in diverse cellular processes, though no immediate functional relationship exists with neighbouring genes.
Protein structure
As of current literature, domain architecture has not been experimentally characterised in detail for this protein. The PIGM protein is predicted (based on computational analysis, not experimental structure determination) to contain multiple transmembrane segments consistent with its function as an endoplasmic reticulum-resident enzyme. Structural modelling suggests regions that may facilitate interaction with donor substrates and the growing GPI precursor, though these have not been definitively mapped through crystallographic or other high-resolution techniques.
Key variants
Pathogenic variants in PIGM typically result in loss of enzyme function, disrupting the mannosylation step required for GPI anchor assembly. Most reported disease-causing variants are missense changes that alter critical amino acid residues, though nonsense and frameshift variants have also been documented. The severity of the resulting glycosylation disorder often correlates with the degree of residual enzyme activity.
Because PIGM follows an autosomal recessive inheritance pattern, individuals with one pathogenic variant and one typical copy generally do not show clinical features. Affected individuals inherit two pathogenic variants, one from each parent. Carrier screening can identify individuals at risk of having children with PIGM-related conditions, particularly in populations where specific variants occur at higher frequencies.
Sample of pathogenic variants
2 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.401del | p.Asn134fs | Pathogenic | ★☆☆☆ | Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency |
c.2T>C | p.Met1Thr | Likely pathogenic | ★☆☆☆ | Inborn genetic diseases |
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 PIGM cause a congenital disorder of glycosylation characterised by impaired production of GPI anchors. Clinical features typically include global developmental delay, intellectual disability, hypotonia (reduced muscle tone), and epilepsy that may be difficult to control with standard treatments. Some affected individuals also experience visual impairment and structural brain abnormalities detectable on neuroimaging.
The age of onset is typically in infancy or early childhood, with neurological features often becoming apparent as affected children fail to meet expected developmental milestones. The condition may be progressive, with some individuals experiencing increased seizure frequency or worsening neurological impairment over time. Management focuses on supportive care, including anti-epileptic medications, physiotherapy, and educational support tailored to the individual's needs.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGM 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
PIGM is included on several NHS Genomic Medicine Service gene panels that guide diagnostic testing for inherited conditions. The gene appears on the Congenital Disorders of Glycosylation panel, reflecting its established role in this group of metabolic disorders. It is also listed on the Early Onset or Syndromic Epilepsy panel and the Likely Inborn Error of Metabolism panel, both with green (high confidence) classification, indicating strong evidence for its clinical utility in diagnosing individuals with these presentations.
Additionally, PIGM features on the Undiagnosed Metabolic Disorders panel, supporting its inclusion in genomic investigations for patients with unexplained metabolic or neurological phenotypes. These panel memberships facilitate access to genetic testing through the NHS for eligible individuals presenting with compatible clinical features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
There is no specific dietary intervention that can modify the severity or progression of PIGM-related glycosylation disorders. General principles of supportive nutrition apply, including ensuring adequate caloric intake and micronutrient status to support overall health in individuals with neurological conditions. Some families, in discussion with NHS dietitians or epilepsy specialists, explore modified diets as part of epilepsy management, but evidence for effectiveness in GPI anchor deficiency disorders remains limited.
Physiotherapy and occupational therapy may support motor development and functional abilities in affected individuals. Maintaining a consistent sleep schedule and avoiding known seizure triggers can be helpful for some people with epilepsy, though these considerations are part of general epilepsy management rather than specific to PIGM-related conditions.
Supplement considerations
No dietary supplement has been shown to restore GPI anchor biosynthesis in individuals with PIGM variants or to prevent the neurological features of the associated glycosylation disorder. Some families and clinicians have explored various supplements as adjuncts to standard care, but conclusive evidence supporting their efficacy is lacking.
Anyone considering supplements for a child or family member with a PIGM-related condition should discuss this with their healthcare team. Supplements can interact with anti-epileptic medications and other treatments, and their use should be coordinated within the broader management plan.
Frequently asked questions
What does the PIGM gene do?
PIGM encodes an enzyme that catalyses an early mannosylation step in the biosynthesis of GPI anchors, glycolipid structures that attach over 150 different proteins to cell membranes. These anchored proteins perform diverse roles in cell signalling, immune function, and development.
How is PIGM inherited?
PIGM follows an autosomal recessive inheritance pattern. This means an individual must inherit two pathogenic variants, one from each parent, to develop a PIGM-related condition. Carriers, with one pathogenic variant and one typical copy, generally do not show symptoms.
What conditions are associated with PIGM variants?
Pathogenic variants in PIGM cause a congenital disorder of glycosylation characterised by developmental delay, intellectual disability, hypotonia, and seizures. Features typically become apparent in infancy or early childhood, and the condition can be progressive.
Is PIGM testing available on the NHS?
Yes, PIGM is included on several NHS Genomic Medicine Service panels, including those for congenital disorders of glycosylation, early onset or syndromic epilepsy, and likely inborn errors of metabolism. Testing is available for individuals meeting clinical criteria for these panels.
Can lifestyle changes help with PIGM-related conditions?
No specific diet or lifestyle modification has been proven to prevent or substantially alter the course of PIGM-related glycosylation disorders. Management focuses on supportive care, seizure control, and therapies to support development and function.