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MPI
mannose phosphate isomerase
MPI is located on the long (q) arm of chromosome 15, at band 15q24.1. Arm ratio per GRCh38 - banding schematic.
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Overview
MPI is located on chromosome 15 and encodes an enzyme that plays a central role in glycosylation, the process by which cells attach complex sugar molecules to proteins. Glycosylation is essential for proper protein folding, stability, and function throughout the body. The mannose phosphate isomerase enzyme catalyses the reversible conversion of mannose-6-phosphate to fructose-6-phosphate, a reaction that connects mannose metabolism to the synthesis of GDP-mannose.
GDP-mannose serves as a sugar donor during N-glycosylation, where carbohydrate structures are assembled and transferred to newly synthesised proteins. When MPI function is compromised, cells cannot maintain adequate GDP-mannose levels, resulting in incomplete or abnormal protein glycosylation that affects multiple organ systems.
What the gene does
Mannose phosphate isomerase functions as a cytosolic enzyme that participates in the interconversion of hexose phosphates within cellular carbohydrate metabolism. The protein catalyses the isomerisation of mannose-6-phosphate to fructose-6-phosphate, allowing mannose derived from dietary sources or cellular breakdown processes to enter glycolytic pathways or be channelled toward GDP-mannose biosynthesis.
The enzyme operates within a metabolic network that supplies precursors for both energy production and the synthesis of glycan structures. By maintaining the balance between different hexose phosphate pools, mannose phosphate isomerase helps ensure that cells have sufficient GDP-mannose available for the glycosylation machinery in the endoplasmic reticulum and Golgi apparatus. Disruption of this enzymatic activity reduces GDP-mannose availability, leading to hypoglycosylation of serum glycoproteins and cellular proteins that depend on mannose-containing oligosaccharide chains for proper function and trafficking.
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Chromosome location
MPI is located on the long arm of chromosome 15 at position 24.1 (15q24.1). The gene spans approximately 52 kilobases of genomic DNA and contains multiple exons that encode the 423-amino-acid mannose phosphate isomerase protein. This chromosomal region contains several other genes involved in metabolic processes, though MPI is the only gene in this locus directly associated with congenital disorders of glycosylation.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in MPI follow an autosomal recessive inheritance pattern, meaning that two altered copies of the gene (one inherited from each parent) are required to cause disease. The variant spectrum includes missense changes that reduce enzymatic activity, as well as nonsense and frameshift variants that eliminate protein function. Specific variants may affect enzyme stability, substrate binding, or catalytic efficiency, all of which compromise the protein's ability to maintain adequate GDP-mannose levels for cellular glycosylation processes.
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.1001_1002dup | p.Leu335fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.1022del | p.Pro341fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.1120C>T | p.Gln374Ter | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.251C>G | p.Ser84Ter | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.657del | p.Ile220fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.679G>T | p.Gly227Ter | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.713del | p.Leu238fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.718C>T | p.Gln240Ter | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.830_831del | p.Ala277fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-congenital disorder of glycosylation |
c.969_970del | p.Phe324fs | Pathogenic/Likely pathogenic | ★★☆☆ | MPI-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 MPI cause congenital disorder of glycosylation type Ib (CDG-Ib), a rare metabolic condition affecting protein glycosylation. Individuals with this disorder typically present in infancy with gastrointestinal symptoms including chronic diarrhoea, vomiting, and protein-losing enteropathy that can lead to failure to thrive. Hepatic involvement is common, with manifestations ranging from elevated liver enzymes to fibrosis and cirrhosis. Some affected individuals develop hypoglycaemia and coagulation abnormalities due to reduced synthesis of properly glycosylated clotting factors. Unlike many other congenital disorders of glycosylation, CDG-Ib may be amenable to dietary mannose supplementation in some cases, though clinical management requires specialist metabolic input.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MPI 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
Within the NHS Genomic Medicine Service, MPI appears on multiple PanelApp panels at green (high-evidence) status. These include the Cholestasis panel, Congenital disorders of glycosylation panel, Likely inborn error of metabolism panel, Neonatal cholestasis panel, and Undiagnosed metabolic disorders panel. The gene is also listed in the Developmental Disorders Genotype-to-Phenotype database (DDG2P). This widespread inclusion reflects the established clinical validity of MPI testing in the context of suspected glycosylation disorders and unexplained liver disease in infancy.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for MPI-related conditions?
MPI-related congenital disorder of glycosylation follows an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition. Parents who each carry one pathogenic variant typically do not show symptoms.
How does MPI deficiency affect the body?
Deficiency of mannose phosphate isomerase reduces the cell's ability to produce GDP-mannose, a molecule required to attach sugar chains to proteins. This leads to abnormal glycosylation of proteins throughout the body, particularly affecting the gastrointestinal tract, liver, and blood clotting systems.
Is genetic testing for MPI available through the NHS?
Yes, MPI testing is available through the NHS Genomic Medicine Service for individuals meeting clinical criteria. The gene is included on multiple diagnostic panels for investigating suspected glycosylation disorders, unexplained liver disease in infancy, and metabolic conditions presenting with gastrointestinal symptoms.