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PMM2
phosphomannomutase 2
PMM2 is located on the short (p) arm of chromosome 16, at band 16p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
PMM2 is located on chromosome 16 and encodes phosphomannomutase 2, an enzyme integral to the glycosylation process. Glycosylation involves attaching chains of sugar molecules to proteins, enabling them to carry out diverse cellular functions. The PMM2 enzyme catalyses a specific conversion step early in this pathway, transforming mannose-6-phosphate into mannose-1-phosphate. This product subsequently contributes to the assembly of sugar chains that modify proteins throughout the body.
Disruptions to PMM2 function impair the glycosylation of numerous proteins, affecting multiple organ systems. Pathogenic variants are inherited in an autosomal recessive pattern, meaning two altered copies of the gene are required for clinical manifestations. The gene's importance is reflected in its inclusion across numerous NHS Genomic Medicine Service panels, encompassing metabolic disorders, neurological conditions, and ciliopathies.
What the gene does
Phosphomannomutase 2 functions as a key enzyme in the early stages of protein glycosylation. The enzyme catalyses the reversible conversion of mannose-6-phosphate to mannose-1-phosphate, a critical step in generating the building blocks needed for constructing oligosaccharide chains. These chains, composed of multiple linked sugar molecules, are later transferred to proteins to create glycoproteins.
Following PMM2 activity, mannose-1-phosphate serves as a precursor for GDP-mannose, a molecule that donates mannose units to growing oligosaccharide structures. Without functional PMM2, cells cannot efficiently produce the mannose-containing sugars required for proper protein modification. Glycoproteins perform essential roles in cell signalling, immune recognition, structural support, and enzyme function. The widespread distribution of glycoproteins throughout the body explains why PMM2 deficiency affects diverse organ systems, including the nervous system, liver, endocrine glands, and skeletal structures.
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Chromosome location
PMM2 is located on the short arm of chromosome 16 at band 16p13.2. This chromosomal region contains numerous genes, and the specific positioning of PMM2 has been well characterised through genomic mapping studies. The gene encodes a protein of 246 amino acids. Structural analysis of the genomic locus reveals the organisation of exons and regulatory sequences that control PMM2 expression across different tissues.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The 246-amino-acid enzyme structure has been resolved, revealing the active site responsible for catalysing the phosphate transfer between mannose-6-phosphate and mannose-1-phosphate. Crystallographic studies have identified the regions of the protein that bind substrate molecules and coordinate the enzymatic reaction. Understanding the three-dimensional structure has helped explain how specific amino acid changes can disrupt enzyme activity, with some variants affecting substrate binding whilst others compromise the catalytic mechanism itself.
Key variants
Over 115 pathogenic variants in PMM2 have been documented in association with congenital disorder of glycosylation. These variants typically reduce or abolish enzyme activity through various mechanisms, including altered protein folding, compromised substrate binding, or disrupted catalytic function. The spectrum of variant severity contributes to clinical variability, with some changes causing profound enzyme deficiency whilst others permit residual activity. Variant interpretation considers biochemical assays, structural modelling, and clinical correlation to establish pathogenicity.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in PMM2 cause congenital disorder of glycosylation Ia, an autosomal recessive condition characterised by multisystem involvement. Clinical features typically include developmental delay, hypotonia, atypical subcutaneous fat distribution, and neurological abnormalities. The severity spectrum ranges from early-onset presentations with profound developmental impairment to milder forms compatible with survival into adulthood. Because glycosylation affects numerous proteins across multiple organ systems, affected individuals may present with hepatic dysfunction, coagulopathy, endocrine abnormalities, skeletal changes, and ocular features. The phenotypic diversity reflects the varying degrees of residual enzyme activity associated with different variant combinations.
Inheritance pattern
Conditions caused by pathogenic PMM2 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
PMM2 holds green classification status across 18 NHS Genomic Medicine Service gene panels, reflecting strong evidence for its clinical validity. These panels include congenital disorders of glycosylation, likely inborn error of metabolism, intellectual disability, and early onset or syndromic epilepsy. Additional panel memberships encompass hereditary neuropathy, foetal anomalies, and various ciliopathy categories. The gene's inclusion in congenital hyperinsulinism and primary ovarian insufficiency panels recognises the endocrine manifestations that can occur. This broad panel representation underscores PMM2's relevance across paediatric, neurological, and metabolic diagnostic pathways within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is PMM2-related congenital disorder of glycosylation inherited?
PMM2-related congenital disorder of glycosylation follows an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the PMM2 gene, one from each parent, to develop the condition. Parents who each carry one pathogenic variant typically do not show symptoms.
Why does PMM2 deficiency affect multiple organ systems?
Glycosylation modifies hundreds of different proteins throughout the body, each performing distinct functions in various tissues. When PMM2 enzyme activity is reduced, many glycoproteins cannot be properly assembled, leading to dysfunction across neurological, hepatic, endocrine, and other systems simultaneously.
Can residual PMM2 enzyme activity influence condition severity?
Research suggests that the degree of remaining enzyme function correlates with clinical severity. Variant combinations that permit some residual PMM2 activity generally associate with milder phenotypes, whilst those causing near-complete enzyme loss tend to produce more severe early-onset presentations.
References
- de la Morena-Barrio ME, Hernández-Caselles T, Corral J. GPI-anchor and GPI-anchored protein expression in PMM2-CDG patients. Orphanet journal of rare diseases. 2013. PMID: 24139637
- Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochimica et biophysica acta. 2009. PMID: 19272306
- Freeze HH. Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients. Biochimica et biophysica acta. 2009. PMID: 19339218
- Haeuptle MA, Hennet T. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Human mutation. 2009. PMID: 19862844
- Gao N, Shang J, Lehrman MA. Analysis of glycosylation in CDG-Ia fibroblasts by fluorophore-assisted carbohydrate electrophoresis: implications for extracellular glucose and intracellular mannose 6-phosphate. The Journal of biological chemistry. 2005. PMID: 15708848
- Adam MP, Bick S, Mirzaa GM. PMM2-CDG. 1993. PMID: 20301289