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DPAGT1
dolichyl-phosphate N-acetylglucosaminephosphotransferase 1
DPAGT1 is located on the long (q) arm of chromosome 11, at band 11q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
DPAGT1 is located on chromosome 11 and encodes dolichyl-phosphate N-acetylglucosaminephosphotransferase 1, an enzyme that initiates the synthesis of dolichol-linked oligosaccharides in the endoplasmic reticulum. This process is the first committed step in N-linked glycosylation, whereby complex sugar chains are attached to newly synthesised proteins. Glycosylation is essential for protein folding, stability, trafficking, and function across virtually all organ systems.
Pathogenic variants in DPAGT1 follow an autosomal recessive inheritance pattern, meaning that individuals require variants in both gene copies to develop clinical features. The resulting enzyme deficiency impairs protein glycosylation broadly, producing a spectrum of phenotypes that can include intellectual disability, epilepsy, congenital myasthenic syndrome, skeletal abnormalities, and arthrogryposis.
What the gene does
The DPAGT1 protein functions as a transmembrane glycosyltransferase anchored in the membrane of the endoplasmic reticulum. It catalyses the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate, generating dolichol-pyrophosphate-N-acetylglucosamine. This reaction represents the initial and rate-limiting step in assembling the dolichol-linked oligosaccharide precursor required for N-glycosylation.
Once the oligosaccharide chain is fully assembled on the dolichol carrier, it is transferred en bloc to asparagine residues on nascent polypeptides as they enter the endoplasmic reticulum. These sugar modifications are crucial for the proper folding, quality control, and trafficking of glycoproteins, including ion channels, receptors, structural proteins, and enzymes. Consequently, DPAGT1 activity supports cellular processes ranging from neurotransmitter receptor function to extracellular matrix assembly.
Because DPAGT1 initiates glycosylation, even partial loss of enzyme activity can have widespread effects on protein maturation and cellular homeostasis, particularly in tissues with high metabolic demands such as the brain and skeletal muscle.
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Chromosome location
DPAGT1 is located on the long arm of chromosome 11 at cytogenetic band 11q23.3. The gene spans approximately 50 kilobases of genomic DNA and comprises multiple exons that encode a 408-amino-acid protein. The chromosomal region 11q23.3 contains several genes involved in development and metabolism, and structural rearrangements or deletions encompassing this region can contribute to contiguous gene syndromes.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The DPAGT1 polypeptide contains 408 amino acids and is predicted to have multiple transmembrane helices that anchor it within the endoplasmic reticulum membrane, positioning the catalytic regions appropriately to access substrates on both sides of the lipid bilayer. Structural studies of related glycosyltransferases suggest that substrate binding and catalytic activity depend on precise spatial organisation of transmembrane and loop regions, though detailed mapping of functional domains within DPAGT1 remains an area of ongoing research.
Key variants
Pathogenic variants in DPAGT1 are typically loss-of-function changes, including missense substitutions that impair enzyme activity, nonsense variants that introduce premature stop codons, and small deletions or insertions that disrupt the reading frame. The severity of clinical manifestations often correlates with the degree of residual enzyme activity, with complete loss of function generally incompatible with viability and hypomorphic alleles producing milder phenotypes.
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.1139C>T | p.Thr380Ile | Pathogenic/Likely pathogenic | ★★☆☆ | DPAGT1-congenital disorder of glycosylation |
c.324G>C | p.Met108Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal anomalies with a likely genetic cause |
c.380_395dup | p.Ser133fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.902G>A | p.Arg301His | Pathogenic/Likely pathogenic | ★★☆☆ | DPAGT1-congenital disorder of glycosylation |
c.1133A>T | p.Asn378Ile | Pathogenic | ★☆☆☆ | Myopathy with tubular aggregates |
c.398C>G | p.Ser133Ter | Pathogenic | ★☆☆☆ | DPAGT1-congenital disorder of glycosylation |
c.732C>A | p.Tyr244Ter | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 13 |
c.737C>A | p.Ser246Ter | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 13 |
c.762_765del | p.Cys255fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 13 |
c.980_981del | p.Ser327fs | Pathogenic | ★☆☆☆ | DPAGT1-congenital disorder of glycosylation |
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 DPAGT1 cause a congenital disorder of glycosylation, historically designated CDG-Ij. Affected individuals present with a broad and variable phenotype that can include early-onset epilepsy, developmental delay, intellectual disability, hypotonia, congenital myasthenic syndrome characterised by muscle weakness and fatigability, and skeletal abnormalities such as arthrogryposis or limb contractures. Some individuals exhibit dysmorphic features or microcephaly. The clinical spectrum reflects the widespread requirement for protein glycosylation across developing and mature tissues, and phenotypic severity varies depending on the specific variants inherited and the degree to which enzyme function is compromised.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DPAGT1 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
DPAGT1 is included on multiple NHS Genomic Medicine Service gene panels with green (high-confidence) classification, reflecting strong evidence for its role in Mendelian disease. These panels include Congenital Disorders of Glycosylation, Early Onset or Syndromic Epilepsy (R59), Intellectual Disability (R29), Congenital Myasthenic Syndrome (R80), Arthrogryposis (R83), Skeletal Dysplasia (R104), Likely Inborn Error of Metabolism (R98), Undiagnosed Metabolic Disorders, Fetal Anomalies (R21), and the Developmental Disorders Genotype-to-Phenotype database (DDG2P). This broad panel representation underscores the gene's relevance across paediatric neurology, metabolic medicine, and clinical genetics pathways within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the DPAGT1 gene do?
DPAGT1 encodes an enzyme that catalyses the first step in building sugar chains that are attached to proteins, a process called N-linked glycosylation. This modification is essential for proteins to fold correctly and function properly throughout the body.
How are DPAGT1-related conditions inherited?
DPAGT1-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit a pathogenic variant from both parents to develop clinical features. Carriers with one variant typically do not show symptoms.
What symptoms are associated with DPAGT1 variants?
Individuals with biallelic DPAGT1 variants may experience developmental delay, intellectual disability, seizures, muscle weakness, skeletal abnormalities such as joint contractures, and other features that vary widely depending on residual enzyme activity.