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GNE
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase
The GNE gene provides instructions for an enzyme essential in the synthesis of sialic acid, a sugar molecule vital for numerous cellular processes throughout the body. The GNE gene encodes an enzyme involved in the multi-step biochemical pathway that produces sialic acid.
GNE is located on the short (p) arm of chromosome 9, at band 9p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The GNE gene, also known as glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase, plays a critical role in human biology by directing the production of an enzyme. This enzyme is found in cells and tissues throughout the body, where it contributes to vital metabolic pathways. Its primary function centres around the synthesis of sialic acid, a complex sugar with diverse biological roles [PMID:32135249].
What the gene does
The enzyme produced from the GNE gene is bifunctional, meaning it performs two distinct enzymatic steps in the sialic acid biosynthesis pathway. Initially, it converts UDP-N-acetylglucosamine (UDP-GlcNAc) into N-acetylmannosamine (ManNAc). Following this, it catalyses the phosphorylation of ManNAc, adding a phosphate group to form ManNAc-6-phosphate. This product is then further processed by other enzymes to complete sialic acid synthesis [PMID:23758064]. Sialic acid is crucial for modifying molecules on cell surfaces, thereby influencing cellular activities such as cell migration, cell-to-cell adhesion, signal transmission between cells, and inflammatory responses [PMID:32135249].
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Chromosome location
The GNE gene is located on the short arm of chromosome 9 at position 9p13.3. This specific genomic location houses the genetic instructions for the GNE enzyme. The gene's position helps in understanding its inheritance patterns and its potential involvement in chromosomal abnormalities.
Protein structure
The GNE protein is composed of 722 amino acids. It features a distinct N-acetylmannosamine kinase region, spanning from amino acids 406 to 722. This region is critical for the kinase activity of the enzyme, allowing it to phosphorylate N-acetylmannosamine during sialic acid synthesis. The bifunctional nature of the GNE enzyme is reflected in its structural organisation.
Key variants
Variants within the GNE gene can lead to alterations in the structure or function of the encoded enzyme. These genetic changes can range from single amino acid substitutions to larger deletions, impacting the enzyme's efficiency or regulatory mechanisms. The specific location and type of variant often determine its clinical consequence.
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.1018C>T | p.Gln340Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
c.1539G>A | p.Trp513Ter | Pathogenic | ★★☆☆ | GNE myopathy |
c.1542dup | p.Asp515fs | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
c.1643del | p.Gly548fs | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
c.1816+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
c.182_185del | p.Ile61fs | Pathogenic/Likely pathogenic | ★★☆☆ | Sialuria |
c.1888G>A | p.Ala630Thr | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
c.556T>C | p.Tyr186His | Pathogenic/Likely pathogenic | ★★☆☆ | Sialuria |
c.723_727del | p.Ile241_Ser242insTer | Pathogenic | ★★☆☆ | GNE myopathy |
c.827T>G | p.Phe276Cys | Pathogenic/Likely pathogenic | ★★☆☆ | GNE myopathy |
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
Variants in the GNE gene are associated with several inherited conditions. One such condition is GNE myopathy, characterised by progressive muscle weakness predominantly affecting adults. Another condition linked to GNE variants is sialuria, which results from impaired regulation of sialic acid production. Additionally, some GNE variants have been implicated in GNE-related thrombocytopenia, a condition involving a lower number of platelets (thrombocytopenia). In this condition, variants in the GNE gene can lead to platelets having reduced levels of sialic acid.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the GNE gene is included on several NHS Genomic Medicine Service national test panels. It is listed on panels for Bleeding and platelet disorders (R90), Congenital disorders of glycosylation, Distal myopathies, Inherited bleeding disorders, Likely inborn error of metabolism (R98), Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82), Lysosomal storage disorder (R276), and Undiagnosed metabolic disorders. This indicates its clinical relevance for diagnosing these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the GNE gene?
The GNE gene provides instructions for an enzyme that is crucial for the biosynthesis of sialic acid. Sialic acid is a sugar molecule found on cell surfaces, where it influences essential cellular functions like cell movement, adhesion, and signalling.
What conditions are associated with GNE gene variants?
Variants in the GNE gene can cause conditions such as GNE myopathy, which involves progressive muscle weakness. They are also linked to sialuria, a metabolic disorder, and GNE-related thrombocytopenia, a condition affecting platelet count.
Where is the GNE gene located?
The GNE gene is found on chromosome 9, specifically at the band position 9p13.3. Its genomic location is important for understanding its genetic context and inheritance.
References
- Klootwijk RD, Savelkoul PJ, Ciccone C. Allele-specific silencing of the dominant disease allele in sialuria by RNA interference. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2008. PMID: 18653764
- Malicdan MC, Noguchi S, Nishino I. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Current opinion in neurology. 2008. PMID: 18769255
- Krause S, Aleo A, Hinderlich S. GNE protein expression and subcellular distribution are unaltered in HIBM. Neurology. 2007. PMID: 17698786
- Penner J, Mantey LR, Elgavish S. Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy. Biochemistry. 2006. PMID: 16503651
- Wopereis S, Abd Hamid UM, Critchley A. Abnormal glycosylation with hypersialylated O-glycans in patients with Sialuria. Biochimica et biophysica acta. 2006. PMID: 16769205
- Nishino I, Malicdan MC, Murayama K. Molecular pathomechanism of distal myopathy with rimmed vacuoles. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2005. PMID: 16550921
- Noguchi S, Keira Y, Murayama K. Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. The Journal of biological chemistry. 2004. PMID: 14707127
- Tomimitsu H, Shimizu J, Ishikawa K. Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. Neurology. 2004. PMID: 15136692
- Eisenberg I, Grabov-Nardini G, Hochner H. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Human mutation. 2003. PMID: 12497639
- Argov Z, Eisenberg I, Grabov-Nardini G. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology. 2003. PMID: 12743242
- Kayashima T, Matsuo H, Satoh A. Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). Journal of human genetics. 2002. PMID: 11916006
- Eisenberg I, Avidan N, Potikha T. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nature genetics. 2001. PMID: 11528398
- Seppala R, Lehto VP, Gahl WA. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. American journal of human genetics. 1999. PMID: 10330343
- Keppler OT, Hinderlich S, Langner J. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science (New York, N.Y.). 1999. PMID: 10334995