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MPDU1
mannose-P-dolichol utilization defect 1
MPDU1 is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
MPDU1 (mannose-P-dolichol utilization defect 1) encodes a protein that participates in the early steps of N-linked glycosylation, a process in which branched sugar chains are attached to newly formed proteins. This modification is essential for proteins to fold correctly, reach their proper locations within cells, and function properly. The gene is located on chromosome 17 and produces a protein of 247 amino acids that resides in the endoplasmic reticulum membrane. Pathogenic variants in MPDU1 cause a rare autosomal recessive disorder characterised by defective glycosylation, which can affect the nervous system, skeletal development, and other organ systems. Because the inheritance pattern is autosomal recessive, individuals typically require pathogenic variants in both gene copies to develop clinical features.
What the gene does
The MPDU1 protein functions as a membrane-embedded enzyme in the endoplasmic reticulum, where it facilitates the transfer of mannose from mannose-phosphate-dolichol to growing oligosaccharide chains. This transfer represents a critical step in building the precursor structure that will eventually be attached to target proteins during N-linked glycosylation. The protein works in coordination with other glycosylation enzymes to ensure that dolichol-linked oligosaccharides are assembled correctly before being transferred to asparagine residues on newly synthesised proteins. Without functional MPDU1, cells cannot efficiently produce properly glycosylated proteins, which compromises the stability and function of numerous glycoproteins throughout the body. The resulting deficiency affects proteins involved in cell signalling, immune function, blood clotting, and structural support, explaining the multi-system nature of disorders caused by MPDU1 deficiency.
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Chromosome location
MPDU1 is located on the short arm of chromosome 17 at position 13.1 (17p13.1). This chromosomal region contains numerous genes involved in development and metabolism. The gene spans a relatively compact genomic region, producing a transcript that encodes a 247-amino-acid protein.
Protein structure
The MPDU1 protein contains two conserved PQ-loop domains that are characteristic of this protein family. PQ-loop 1 spans amino acids 39 to 105, whilst PQ-loop 2 extends from amino acids 159 to 216. These PQ-loop regions are thought to be involved in substrate recognition and enzymatic activity, allowing the protein to interact with mannose-phosphate-dolichol and facilitate mannose transfer. The protein adopts a multi-pass transmembrane configuration that anchors it within the endoplasmic reticulum membrane, positioning the catalytic regions appropriately for interaction with dolichol-linked substrates.
Key variants
Pathogenic variants in MPDU1 are rare and typically result in loss of protein function. Most disease-causing variants are missense changes that disrupt the protein's enzymatic activity or stability, though nonsense and frameshift variants have also been reported. The spectrum of variants reflects the protein's essential role in glycosylation, with most pathogenic changes affecting residues critical for substrate binding or catalytic function.
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.221T>C | p.Leu74Ser | Pathogenic | - | MPDU1-congenital disorder of glycosylation |
c.356T>C | p.Leu119Pro | Pathogenic | - | MPDU1-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
Pathogenic variants in MPDU1 cause congenital disorder of glycosylation type If (CDG-If), a rare multi-system disorder. Affected individuals typically present in infancy or early childhood with developmental delay, intellectual disability, seizures, and feeding difficulties. Skeletal abnormalities, including short stature and bone dysplasia, are common features. Some individuals also experience liver dysfunction, coagulation abnormalities, and gastrointestinal problems. The severity and specific clinical features can vary between affected individuals, even among those with the same variants, reflecting the widespread importance of glycosylation across organ systems.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MPDU1 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
MPDU1 is included on multiple NHS Genomic Medicine Service panels, reflecting its clinical importance in the UK healthcare system. The gene holds green (high evidence) status on the Congenital disorders of glycosylation panel and the DDG2P (Developmental Disorders Genotype-Phenotype Database) panel. It also appears on green-rated panels for Early onset or syndromic epilepsy (R59), Fetal anomalies (R21), Intellectual disability (R29), Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This broad panel representation reflects the diverse clinical presentations associated with MPDU1-related glycosylation defects.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does autosomal recessive inheritance mean for MPDU1?
Autosomal recessive inheritance means that an individual typically needs to inherit a pathogenic variant from both parents to develop clinical features. Carriers, who have one pathogenic variant and one working copy, generally do not experience symptoms but can pass the variant to their children.
How is MPDU1-related congenital disorder of glycosylation diagnosed?
Diagnosis typically involves biochemical testing that reveals abnormal glycosylation patterns in blood proteins, followed by genetic testing to identify pathogenic variants in MPDU1. Clinical evaluation of developmental milestones, neurological function, and skeletal features also contributes to diagnosis.
Why does MPDU1 deficiency affect multiple organ systems?
Because glycosylation is required for proper function of proteins throughout the body, defects in MPDU1 impair glycosylation of numerous proteins involved in brain development, bone formation, blood clotting, and other processes. This widespread impact explains why affected individuals experience symptoms across multiple organ systems.